EA042829B1 - TRIAZOLE N-LINKED CARBAMOYL CYCLOHEXYL ACIDS AS LPA ANTAGONISTS - Google Patents

Description

Cross-reference to related applications

This Application Claims Priority of U.S. Provisional Application

62/607399, filed December 19, 2017, the entire contents of which are hereby incorporated by reference.

The field of technology to which the invention belongs

The present invention relates to new substituted triazole compounds, compositions containing them and methods of using them, for example, for the treatment of disorders associated with one or more lysophosphatidic acid (LPA) receptors.

Prerequisites for the creation of the invention

Lysophospholipids are bioactive lipid mediators of membrane origin, of which one of the most medically important is lysophosphatidic acid (LPA). LPA is not a single molecular form, but a set of endogenous structure variants with fatty acids of various lengths and degrees of saturation (Fujiwara et al., J. Biol. Chem., 2005, 280, 35038-35050). The structural backbone of LPA is derived from glycerol phospholipids such as phosphatidylcholine (PC) or phosphatidic acid (PA).

Lysophosphatidic acids (LPAs) are bioactive lipids (signaling lipids) that regulate various cellular signaling pathways by binding to the same type of G-protein coupled receptors (GPCRs) with 7-transmembrane domains (Chun, J., Hla, T. , Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4 & Zhao, Y. et al., Biochim. Biophys. Acta ( BBA)-Mol. Cell Biol. Of Lipids, 2013, 1831, 86-92). Currently known LPA receptors are referred to as LPA1, LPA ₂ , LPA3, LPA4, LPA ₅ and LPA6 (Choi, JW, Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186; Kihara, Y., et al. , Br. J. Pharmacol., 2014, 171, 3575-3594).

Lysophosphatidic acids (LPAs) have long been known as precursors in phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but it has only recently been shown that lysophosphatidic acids (LPAs) are signaling molecules that are rapidly produced and released by activated cells, especially platelets. in order to act on target cells by acting on specific cell surface receptors (see, for example, Moolenaar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc. Trans. , 2003, 31, 1209-1212). In addition to being synthesized and converted into more complex phospholipids in the endoplasmic reticulum, lysophosphatidic acids (LPAs) can be produced by hydrolysis of existing phospholipids following cell activation; for example, at the sn-2 position, a fatty acid residue is often missing due to deacylation, and only the sn-1 hydroxyl remains esterified with the fatty acid. Moreover, a key enzyme in LPA production, autotaxin (lysoPLD/NPP2), may be the product of an oncogene since many types of tumors activate autotaxin (Brindley, D., J. Cell Biochem. 2004, 92, 900-12). Lysophosphatidic acid (LPA) concentrations have been reported in human plasma and serum, as well as human bronchoalveolar lavage fluid (BALF), including measurements made by sensitive and specific LC/MS and LC/MS/MS methods (Baker et al. Anal Biochem., 2001, 292, 287-295 Onorato et al., J. Lipid Res., 2014, 55, 17841796).

LPA affects a wide range of biological responses, including induction of cell proliferation, stimulation of cell migration and neurite retraction, gap junction termination, and even myxomycete chemotaxis (Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J ., Hla, T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4). The body of knowledge about the biology of LPA continues to grow as more and more cell systems are tested for their ability to respond to LPA. For example, in addition to stimulating cell growth and proliferation, lysophosphatidic acids (LPAs) are now known to promote cellular tension and fibronectin binding at the cell surface, which are important events in wound healing and regeneration (Moolenaar et al., BioEssays, 2004, 26, 870-881). Recently, the anti-apoptotic activity of LPA has been described, and PPARy has recently been reported as a receptor/target for LPA (Simon et al., J. Biol. Chem., 2005, 280, 14656-14662).

Fibrosis is the result of an uncontrolled tissue healing process leading to excessive accumulation and insufficient resorption of the extracellular matrix (ECM), which ultimately leads to end-stage organ failure (Rockey, D.C, et al., New Engl. J. Med, 2015, 372 , 1138-1149). The LPA1 receptor has been reported to be overexpressed in patients with idiopathic pulmonary fibrosis (IPF). LPA1 receptor knockout mice were protected from bleomycin-induced pulmonary fibrosis (Tager et al., Nature Med., 2008, 14, 45-54). The LPA1 antagonist BMS-986020 has been shown to significantly reduce FVC (forced vital capacity) in a 26-week clinical trial in patients with IPF (Palmer et al., Chest, 2018, 154, 1061-1069). Inhibitors of the LPA pathway (eg, an LPA1 antagonist) have been shown to be chemoprophylactic antifibrotic agents in the treatment of hepatocellular carcinoma in a rat model (Nakagawa et al., Cancer Cell, 2016, 30, 879-890).

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Thus, LPA1 receptor antagonization may be useful in the treatment of fibrosis such as pulmonary fibrosis, liver fibrosis, renal fibrosis, arterial fibrosis, and systemic sclerosis, and thus diseases resulting from fibrosis (pulmonary fibrosis - idiopathic pulmonary fibrosis [IPF ], liver fibrosis - non-alcoholic steatohepatitis (NASH), kidney fibrosis - diabetic nephropathy, systemic sclerosis - scleroderma, etc.).

Brief description of the invention

The present invention relates to novel substituted triazole compounds, including stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, which are useful as antagonists against one or more lysophosphatidic acid (LPA) receptors, especially the LPA ₁ receptor.

The present invention also relates to procedures and intermediates for the preparation of the compounds of the present invention.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof.

The compounds of the invention can be used in the treatment of conditions in which LPA is involved.

The compounds of the present invention can be used in therapy.

The compounds of the present invention can be used for the manufacture of a medicament for the treatment of a condition in which inhibition of the physiological activity of LPA is beneficial, for example, diseases in which the LPA receptor is involved, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom. diseases.

In another aspect, the present invention relates to a method for the treatment of organ fibrosis (liver, kidney, lung, heart, etc., as well as skin), liver disease (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative insufficiency , non-alcoholic steatohepatitis (NASH), hypofunction of the liver, impaired hepatic blood flow, etc.), cell proliferative disease [cancer (solid tumor, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia ( CLL), etc.) and invasive cancer cell metastasis, etc.], inflammatory diseases (psoriasis, nephropathy, pneumonia, etc.), diseases of the gastrointestinal tract (irritable bowel syndrome (IBS), inflammatory disease bowel disease (IBD), abnormal pancreatic secretion, etc.), kidney disease, urinary tract disease (benign prostatic hyperplasia or symptoms associated with neurogenic bladder, spinal cord tumor or herniated disc, spinal stenosis, symptoms, resulting from diabetes, lower urinary tract disease (lower urinary tract obstruction, etc.), lower urinary tract inflammatory disease, dysuria, frequent urination, etc.), pancreatic disease, abnormal angiogenesis related disease (arterial obstruction, etc.), scleroderma, brain disease (cerebral infarction, intracerebral hemorrhage, etc.), neuropathic pain, peripheral neuropathy, etc., eye disease (age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), scarring pemphigoid, scarring after glaucoma filtration surgery, etc.).

In another aspect, the present invention relates to a method of treating diseases, disorders or conditions in which activation of at least one LPA receptor by LPA contributes to the symptomatology or progression of the disease, disorder or condition. These diseases, disorders, or conditions may be due to one or more of genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and/or traumatic etiologies.

In yet another aspect, the present invention relates to a method of treating kidney fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis, and systemic sclerosis, comprising administering to a patient in need of such treatment a compound of the present invention as described above.

In one aspect, the present invention relates to the methods, compounds, pharmaceutical compositions and drugs described herein, which contain LPA receptor antagonists, in particular LPA1 antagonists.

The compounds of the invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one or two, other agents.

These and other features of the invention will be set forth in expanded form as the disclosure proceeds.

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Detailed description of the invention

I. Compounds of the invention.

In one aspect, the present invention relates in particular to compounds of formulas (IV)

or their pharmaceutically acceptable salts, where

R ^2a represents hydrogen, chlorine, fluorine or C _1-4 alkyl;

R ³ is hydrogen or C _1-6 alkyl;

R ⁴ is Aralkyl, C _3-8 cycloalkyl, phenyl, -(C _1-6 alkylene)-(C _3-8 cycloalkyl) or -(C _1-6 alkylene)-(phenyl); where each of alkyl, cycloalkyl, and phenyl, by itself or as part of another moiety, is independently substituted with 0-3 R ⁸ ;

R ⁶ is hydrogen or C1-6 alkyl or each R ⁸ is independently deuterium, halo, hydroxy, amino, cyano, O 1-6 alkyl or C _1-6 deuterated alkyl (fully or partially deuterated).

In one of the previous embodiments, R ⁶ is methyl or ethyl.

In one embodiment of the present invention, the compound is selected from any compound of the examples provided in the description, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or solvate.

In yet another embodiment of the present invention, the compound is selected from the compounds of examples 1-240, presented in the description, or their stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates.

In yet another embodiment of the present invention, the compound is selected from the compounds of examples 1-145 presented in the description, or their stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates.

In one embodiment of the present invention, the compound is selected from:

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or their pharmaceutically acceptable salts.

In one embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

In one embodiment of the present invention, the compound is selected from:

- 4 042829 or their pharmaceutically acceptable salts.

In yet another embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

In yet another embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

In yet another embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

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In yet another embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

In yet another embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

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In yet another embodiment of the present invention, the compound is selected from:

or their pharmaceutically acceptable salts.

In one embodiment, the compounds of the present invention have hLPA1 IC ₅₀ values of <5000 nM using a functional LPA1 antagonist assay; in another embodiment, the compounds of the present invention have hLPA1 IC ₅₀ values <1000 nM; in another embodiment, the compounds of the present invention have hLPA1 IC ₅₀ values <500 nM; in another embodiment, the compounds of the present invention have hLPA1 IC ₅₀ values <200 nM; in another embodiment, the compounds of the present invention have IC ₅₀ hLPA ₁ values <100 nM; in another embodiment, the compounds of the present invention have hLPA1 IC50 values <50 nM.

II. Other embodiments of the invention.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is an antagonist at least one LPA receptor. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is an LPA1 antagonist. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is an LPA2 antagonist. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is an LPA3 antagonist.

In some embodiments, provided herein are compounds selected from active metabolites, tautomers, pharmaceutically acceptable salts, or solvates of a compound of formula (I).

In another embodiment, the present invention relates to a composition containing at least one of the compounds of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt or solvate.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

In yet another embodiment, the present invention relates to a process for preparing a compound of the present invention.

In yet another embodiment, the present invention relates to an intermediate compound for obtaining the compounds of the present invention.

In yet another embodiment, the present invention relates to a pharmaceutical composition further comprising an additional therapeutic agent(s).

In yet another embodiment, the present invention relates to a method of treating a condition associated with LPA receptor mediated fibrosis, comprising administering to a patient in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate. As used herein, the term patient encompasses all mammalian species.

In yet another embodiment, the present invention relates to a method of treating a disease, disorder or condition associated with lysophosphatidic acid receptor 1 (LPA1) dysregulation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer , or a pharmaceutically acceptable salt or solvate. In one embodiment of the method, the disease, disorder, or condition is associated with pathological fibrosis, transplant rejection, cancer, osteoporosis, or inflammatory disorders. In one embodiment of the method, the pathological fibrosis is fibrosis of the lungs, liver, kidneys, heart, dermis, eyes, or pancreas. In one embodiment of the method, the disease, disorder, or condition is

- 7 042829 idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease and systemic sclerosis. In one embodiment of the method, the cancer is bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genital, genitourinary, head, kidney, larynx , liver, lung, muscle, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, colon, stomach, testis, or thyroid gland.

In yet another embodiment, the present invention provides a method of treating fibrosis in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. In one embodiment of the method, the fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), chronic kidney disease, diabetic kidney disease, and systemic sclerosis.

In yet another embodiment, the present invention relates to a method of treating pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, bowel fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, colorectal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer-related pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagenosis, atherosclerosis, Raynaud's phenomenon, or neuropathic pain in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate.

As used herein, the term treatment or therapy encompasses the treatment of a disease state in a mammal, in particular a human, and includes (a) inhibition of the disease state, i.e. cessation of its development; and/or (b) alleviating the disease state, i. e. causing regression of the disease state. As used herein, the term treatment or therapy also includes the protective treatment of a disease state to reduce and/or minimize the risk and/or reduce the risk of recurrence of the disease state by administering to a patient a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer thereof. , tautomer, pharmaceutically acceptable salt or solvate. Patients may be selected for such protective therapy based on factors known to increase the risk of developing a clinical disease state compared to the general population. For protective treatment, signs of the clinical disease state may or may not yet be present. Protective treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment aimed at reducing or minimizing the risk of a disease state in a patient who has not yet had a clinical disease state, while secondary prevention is defined as minimizing or reducing the risk of recurrence or reappearance of the same or similar disease. clinical disease.

The present invention may be embodied in other specific forms without departing from its spirit or essential features. This invention covers all combinations of the preferred aspects of the invention noted in this document. It is understood that any and all embodiments of the present invention may be considered in conjunction with any other embodiment or embodiments to describe additional embodiments. Also, it should be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, it is contemplated that any element of an embodiment may be combined with any or all of the other elements from any embodiment to describe an additional embodiment.

III. Chemistry.

Throughout the specification and the appended claims, a given chemical formula or name is intended to encompass all of their stereo and optical isomers and racemates, if such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated by the present invention. The cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separate isomeric forms. The compounds of the present invention may be isolated in optically active or racemic forms. Optically active forms can be obtained by resolution of racemic forms or by synthesis from optically active parent compounds. All methods used to obtain the compounds of the present invention and the intermediates obtained therein are considered part of the present invention. When enantiomeric or diastereomeric products are obtained, they can be separated by conventional means such as chromatography or fractional crystallization. Depending on the process conditions, the end products of the present invention are obtained in either free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If desired, one form of the compound can be converted to another form. The free base or acid may be converted to a salt; the salt may be converted to the free compound or another salt; the mixture of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free form and salts can exist in a variety of tautomeric forms in which hydrogen atoms move to other parts of the molecules and the chemical bonds between the atoms of the molecules rearrange accordingly. It should be understood that all tautomeric forms, if they may exist, are included in the invention.

The term stereoisomer refers to isomers of identical composition that differ in the arrangement of their atoms in space. Examples of stereoisomers are enantiomers and diastereomers. The term enantiomer refers to a single pair of molecules that are non-overlapping mirror images of each other. The term diastereomer refers to stereoisomers that are not mirror images. The term racemate or racemic mixture refers to a composition consisting of equimolar amounts of two enantiomeric compounds, where the composition is devoid of optical activity.

The symbols R and S represent the configuration of substituents around the chiral carbon atom(s). The isomeric characteristics R and S are used as described herein to indicate the configuration(s) of atoms relative to the parent molecule and are intended to be used as described in the literature (IUPAC Guidelines 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996) ).

The term chiral refers to such a structural characteristic of a molecule that it is impossible to superimpose it on its mirror image. The term homochiral refers to the level of enantiomeric purity. The term optical activity refers to the degree to which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarized light.

As used herein, the term alkyl or alkylene is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. While alkyl denotes a monovalent saturated aliphatic radical (such as ethyl), alkylene denotes a divalent saturated aliphatic radical (such as ethylene). For example, (C ₁ -C ₁ o) alkyl or C 1_ ₁₀ alkyl includes C 1 , C 2 , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C u alkyl groups. The term (C ₁ -C ₁₀ )alkylene or C1_ ₁₀ alkylene is intended to include C1, C2, C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C9 and C ₁₀ alkylene groups. In addition, for example, (C ₁ -C ₆ )alkyl or C ₁ . ₆ alkyl means alkyl having 1-6 carbon atoms; and (C1-C ₆ )alkylene or C ₁ . ₆ alkylene means alkylene having 1-6 carbon atoms; and (C1-C ₄ )alkyl or C ₁ . ₄ alkyl means alkyl having 1-4 carbon atoms; and (C1-C ₄ )alkylene or C ₁ . ₄ alkylene means alkylene having 1-4 carbon atoms. The alkyl group may be unsubstituted or substituted with at least one hydrogen atom substituted with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, isobutyl, t-butyl) and pentyl (e.g. n -pentyl, isopentyl, neopentyl). In the case of C ₀ -alkyl or C ₀ -alkylene, this means a direct bond. In addition, the term alkyl, by itself or as part of another group such as alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, and haloalkoxy, can be alkyl having 1-4 carbon atoms, or 1-6 carbon atoms. carbon, or 1-10 carbon atoms.

Heteroalkyl refers to an alkyl group in which one or more carbon atoms has been replaced by a heteroatom such as O, N, or S. For example, if the carbon atom of the alkyl group that is attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, an alkoxy group (for example, -OCH _{3 ,} etc.), an alkylamino (for example, -NHCH ₃ , -N(CH ₃ ) ₂ , etc.) or a thioalkyl group (for example , -SCH ₃ ). If the non-terminal carbon atom of an alkyl group that is not attached to the parent molecule is replaced by a heteroatom (for example, O, N, or S), the resulting heteroalkyl groups are, respectively, an alkyl ether (for example, -CH2CH2-O-CH ₃ and t .d.), alkylaminoalkyl (eg -CH2NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ etc.) or thioalkyl ether (eg -CH2-S-CH ₃ ). When the terminal carbon of an alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH ₂ CH ₂ -OH), an aminoalkyl group (e.g. -CH2NH2) or an alkylthiol group (eg -CH2CH2-SH). The heteroalkyl group may contain, for example, 1-20 carbon atoms, 1-10 carbon atoms, or 1-6 carbon atoms. (C ₁ -C ₆ )heteroalkylα group means a heteroalkyl group,

- 9 042829 containing 1-6 carbon atoms.

The term alkenyl or alkenylene is intended to include straight or branched hydrocarbon chains having a specified number of carbon atoms and one or more, preferably one or two, carbon-carbon double bonds which may occur at any stable point along the chain. For example, the term (C ₂ -C ₆ )alkenyl or C ₂ _ ₆ alkenyl (or alkenylene) is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.

The term alkynyl or alkynylene is intended to include straight or branched hydrocarbon chains having one or more, preferably one to three, carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, the term (C ₂ -C ₆ )alkynyl or C ₂ _ ₆ alkynyl (or alkynylene) is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl and hexynyl.

As used herein, the term arylalkyl (aka aralkyl), heteroarylalkyl, carbocyclylalkyl, or heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms attached to a carbon atom, typically a terminal or sp ³ carbon atom, is substituted, respectively, aryl, heteroaryl, carbocyclyl or heterocyclyl radical. Exemplary arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. An arylalkyl, heteroarylalkyl, carbocyclylalkyl or heterocyclylalkyl group may contain 4-20 carbon atoms and 0-5 heteroatoms, for example, the alkyl moiety may contain 1-6 carbon atoms.

As used herein, the term benzyl refers to a methyl group in which one of the hydrogen atoms is substituted by a phenyl group, said phenyl group being optionally substituted with 1-5 groups, preferably 1-3 groups, OH, OCH ₃ , Cl, F, Br , I, CN, NO2, NH ₂ , N(CH3)H, N(CH3) ₂ , CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O) ₂ CH3, CH3, CH2CH3, CO2H and CO ₂ CH ₃ . Benzyl may also be represented by the formula Bn.

The term alkoxy or alkyloxy refers to an -O-alkyl group. The term (C ₁ -C ₆ )alkoxy or C ₁ . ₆ alkoxy (or alkyloxy) is intended to include C1, C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy. Similarly, alkylthio or thioalkoxy is an alkyl group as defined above with the number of carbons attached via a sulfur bridge as indicated; for example, methyl-S- and ethyl-S-.

The term alkanoyl or alkylcarbonyl, whether used alone or as part of another group herein, refers to alkyl bonded to a carbonyl group. For example, alkylcarbonyl can be represented by alkyl-C(O)-. The term (C1-C ₆ )alkylcarbonyl (or alkylcarbonyl) is intended to include C1, C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl-C(O) groups.

The term alkylsulfonyl or sulfonamide, used herein alone or as part of another group, refers to an alkyl or amino group linked to a sulfonyl group. For example, an alkylsulfonyl may be represented by -S(O) ₂ R' while a sulfonamide may be represented by -S(O) ₂ NR ^c R ^d . R' is (C1-C ₆ )alkyl; and R ^c and R ^d are as defined below for amino.

The term carbamate, used herein alone or as part of another group, refers to the oxygen associated with the amido group. For example, the carbamate can be represented by N(R ^c R ^d )-C(O)-O-, and R ^c and R ^d are as defined below for amino.

The term amido, as used herein alone or as part of another group, refers to an amino group linked to a carbonyl group. For example, amido can be represented by N(R ^c R ^d )-C(O)-, and R ^c and R ^d are the same as defined below for amino.

The term amino is defined as -NR ^c1 R ^c2 where R ^c1 and R ^c2 are independently H or C1.6αkyl; or alternatively R ^c1 and R ^c2 taken together with the atoms to which they are attached form a 3-8 membered heterocyclic ring which is optionally substituted with one or more groups selected from halo, cyano, hydroxyl, amino, oxo, C1. ₆ alkyl, alkoxy and aminoalkyl. When R ^c1 or R ^c2 (or both) is C ₁ . ₆ alkyl, amino group may also be referred to as alkylamino. Examples of the alkylamino group include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. In one embodiment, the amino is -NH2.

The term aminoalkyl refers to an alkyl group in which one of the hydrogen atoms is replaced by an amino group. For example, aminoalkyl can be represented as N(R ^c1 R ^c2 )-alkylene-. It is assumed that Ύ-€ ₆ or C1.6 aminoalkyl (or aminoalkyl) includes C1, _C2 , _C3 , _C4 , _C5 and C6 aminoalkyl groups.

The term halogen or halo, used herein alone or as part of another group, refers to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred.

- 10 042829

Haloalkyl is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups containing the indicated number of carbon atoms substituted with one or more halogens. The term is (C1-C ₆ )haloalkyl or C ₁ . ₆ haloalkyl (or haloalkyl) is intended to include C1, _C2 , _C3 , _C4 , _C5 and _C6 haloalkyl groups. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include fluoroalkyl, which is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with one or more fluorine atoms. As used herein, the term polyhaloalkyl refers to an alkyl group as defined above which has 2-9, preferably 2-5 halo substituents, such as F or Cl, preferably F, such as, for example, polyfluoroalkyl, such as CF ₃ CH ₂ , CF ₃ or CF3CF2CH2.

Haloalkoxy or haloalkyloxy is a haloalkyl group as defined above, having the indicated number of carbon atoms attached through an oxygen bridge. For example, the term (C ₁ -C ₆ )haloalkoxy or C ₁ . ₆ haloalkoxy is designed to include C1, _C2 , _C3 , _C4 , _C5 and _C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, a haloalkylthio or thiohaloalkoxy is a haloalkyl group, as defined above, having the indicated number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-. As used herein, the term polyhaloalkyloxy refers to an alkoxy or alkyloxy group as defined above which has 2 to 9, preferably 2 to 5 halo substituents, such as F or Cl, preferably F, such as polyfluoroalkoxy, e.g. CF ₃ CH ₂ O , CF ₃ O or CF3CF2CH2O.

The term hydroxyalkyl is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with one or more hydroxyl (OH). It is assumed that (C1-C ₆ )hydroxyalkyl (or hydroxyalkyl) includes C1, C ₂ , C ₃ , C ₄ , C ₅ and C ₆ hydroxyalkyl groups.

The term cycloalkyl refers to cyclized alkyl groups, including mono-, bi-, or polycyclic ring systems. The term (C ₃ -C ₈ )cycloalkyl or C ₃ _ ₈ cycloalkyl is intended to include C ₃ , C ₄ , C ₅ , C ₆ , C7 and C ₈ cycloalkyl groups, including monocyclic, bicyclic and polycyclic rings. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl as well as spiro and bridged cycloalkyl groups are included in the definition of cycloalkyl.

The term cycloheteroalkyl refers to cyclized heteroalkyl groups, including mono-, bi-, or polycyclic ring systems. The term (C3-C7)cycloheteroalkyl or _{C3-7cycloheteroalkyl} is intended to include _C3 , _C4 , _C5 , _C6 and C7 cycloheteroalkyl groups. Examples of cycloheteroalkyl groups include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. Branched cycloheteroalkyl groups such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl and pyrazinylmethyl are included within the definition of cycloheteroalkyl.

As used herein, the term carbocycle, carbocyclyl, or carbocyclic residue is intended to include any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10- , 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadenyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [ 4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of a carbocycle (eg [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise indicated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and indanyl. When the term carbocyclyl is used, it is intended to include the term aryl. A bridging ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that the bridge always transforms a monocyclic ring into a tricyclic ring. When the ring is bridged, the substituents specified for the ring may also be present on the bridge.

In addition, the term carbocyclyl, including cycloalkyl and cycloalkenyl, used alone or as part of another group herein, includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl , bicyclic alkyl and tricyclic alkyl, containing in

- 11 042829 a total of 3-20 carbon atoms forming rings, preferably 3-10 carbon atoms or

3-6 carbon atoms forming a ring and which can be fused with 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

L . L , 00 .um

T wherein any of these groups may be optionally substituted with 1-4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and /or alkylthio, and/or any of the alkyl substituents.

As used herein, the term bicyclic carbocycle or bicyclic carbocyclic group means a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and is composed of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to the second ring; and the second ring is a 5- or 6-membered carbon ring that is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group can be attached to its side group at any carbon atom, resulting in a stable structure. The bicyclic carbocyclic group described herein may be substituted at any carbon atom as long as the resulting compound is stable. Examples of the bicyclic carbocyclic group include, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

The term aryl, used herein alone or as part of another group, refers to monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons, including, for example, phenyl, naphthyl, anthracenyl, and phenanthranyl. Aryl moieties are well known and are described in, for example, Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, ^13th Edition, John Wiley & Sons, Inc., New York (1997). In one embodiment, the term aryl means monocyclic and bicyclic aromatic groups containing 6-10 carbon atoms in the ring portion (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl). For example, C ₆ -, or C ₁₀ -aryl, or C _6-10 aryl refers to phenyl and naphthyl. Unless otherwise indicated, aryl, C ₆ - or C ₁₀ -aryl, C _6-10 aryl or aromatic residue may be unsubstituted or substituted with 1-5 groups, preferably 1-3 groups selected from -OH, -OCH ₃ , - Cl, -F, -Br, -I, -CN, -NO ₂ , -NH ₂ , -N(CH3)H, -N(CH3)2, -CF3, -OCF3, -C(O)CH3, - SCH3, -S(O)CH3, -S(O)2CH3, -CH3, -CH2CH3, -CO2H and -CO2CH3.

As used herein, the term benzyl refers to a methyl group in which one of the hydrogen atoms is substituted by a phenyl group, said phenyl group being optionally substituted with 1-5 groups, preferably 1-3 groups, OH, OCH3, Cl, F, Br , I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H and CO2CH3.

As used herein, the term heterocycle, heterocyclyl, or heterocyclic group means a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11- , 12-, 13- or 14-membered polycyclic (including bicyclic and tricyclic) heterocyclic ring which is saturated or partially unsaturated and which contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above heterocyclic rings is fused to a carbocyclic or aryl (eg, benzene) ring. That is, the term heterocycle, heterocyclyl, or heterocyclic group includes non-aromatic ring systems such as heterocycloalkyl and heterocycloalkenyl. The nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O)p where p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or another substituent, if specified). A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom, resulting in a stable structure. The heterocyclic rings described herein may be substituted at a carbon atom or a nitrogen atom if the resulting compound is stable. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Examples of heterocyclyl include, but are not limited to, azetidinyl, piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydrofinolin, morpholinyl, dihydrofuro[2,3b ]tetrahydrofuran.

As used herein, the term bicyclic heterocycle or bicyclic heterocyclic group means a stable 9- or 10-membered heterocyclic ring system that contains two fused rings and is composed of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring containing a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo ring, each of which is fused with second ring. The second ring is a 5- or 6-membered monocyclic ring that is saturated, partially unsaturated, or unsaturated, and contains a 5-membered heterocycle, a 6-membered heterocycle, or a carbocycle (provided that the first ring is not a benzo when the second ring is a carbocycle).

The bicyclic heterocyclic group can be attached to its side group via any heteroatom or carbon atom, resulting in a stable structure. The bicyclic heterocyclic group described herein may be substituted at a carbon atom or a nitrogen atom if the resulting compound is stable. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Examples of the bicyclic heterocyclic group include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7 ,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanil, 1,2,3,4-tetrahydroquinoxalinyl and 1,2,3,4 tetrahydroquinazolinyl.

Bridged rings are also included in the definition of a heterocycle. A bridged ring is formed when one or more, preferably one to three, atoms (ie C, O, N or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. Note that bridging always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, the substituents listed for the ring may also be present in the bridge.

As used herein, the term heteroaryl means stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom in the heterocycle, such as a sulfur, oxygen or nitrogen atom. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (ie, N or NR, where R is H or another substituent, if specified). The nitrogen and sulfur heteroatoms may optionally be oxidized (ie, N^O and S(O) _p , where p is 0, 1, or 2).

Examples of heteroaryl include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-linanyl, chromium, decahydroquinolinyl, 2H,6H-1,5,2dithiazinyl, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinyl, isobenzofuranyl, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- оксадиазолил, оксазолидинил, оксазолил, оксазолопиридинил, оксазолидинилперимидинил, оксиндолил, пиримидинил, фенантридинил, фенантролинил, феназинил, фенотиазинил, феноксатианил, феноксазинил, фталазинил, птеридинил, пуринил, пиразинил, пиразолидинил, пиразолинил, пиразолопиридинил, пиразолил, пиридазинил, пиридооксазолил, пиридоимидазолил, пиридотиазолил, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1, 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

Examples of 5-10 membered heteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H -индазолил, бензофуранил, бензотиофуранил, бензтетразолил, бензотриазолил, бензизоксазолил, бензоксазолил, оксиндолил, бензоксазолинил, бензтиазолил, бензизотиазолил, изатиноил, изохинолинил, октагидроизохинолинил, изоксазолопиридинил, хиназолинил, хинолинил, изотиазолопирридинил, тиазолопиридинил, оксазолопиридинил, имидазолопиридинил и пиразолопиридинил.

Examples of 5-6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl,

- 13 042829 pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl and triazolyl. In some embodiments, heteroaryl is selected from benzthiazolyl, imidazolpyridinyl, pyrrolopyridinyl, quinolinyl, and indolyl.

Unless otherwise indicated, carbocyclyl or heterocyclyl includes one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as, for example, aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings), e.g.

and may be optionally substituted through available carbon or nitrogen atoms (where applicable) with 1, 2 or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cyclo heteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heterocyano, hydroxy, nitroalkylthiol гетероарилтио, арилтиоалкила, алкоксиарилтио, алкилкарбонила, арилкарбонила, алкиламинокарбонила, ариламинокарбонила, алкоксикарбонила, аминокарбонила, алкилкарбонилокси, арилкарбонилокси, алкилкарбониламино, арилкарбониламино, арилсульфинила, арилсульфинилалкила, арилсульфониламино и арилсульфонаминокарбонила, и/или любого из алкильных заместителей, изложенных в настоящем документе.

When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are used as part of another group, the number of carbon atoms and ring members is the same as defined in the terms themselves. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio, and the like, each independently contains a number of carbon atoms that are the same as defined for the term alkyl, such as 1-4 carbons, 1-6 carbons, 1-10 carbons, etc. Similarly, each cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, and the like. independently contains ring members that are the same as defined for the terms cycloalkyl, heterocyclyl, aryl, and heteroaryl, such as 3-6-membered, 4-7-membered, 6-10-membered, 5-10-membered, 5- or 6-membered, etc.

In accordance with convention used in the art, a bond indicating a heavy line, such as used in structural formulas herein, depicts a bond that is the point of attachment of a fragment or substituent to the core or backbone structure.

According to the convention used in the art, a wavy or curved bond in a Z' structural formula such as ^{x γ} > is used to denote the stereogenic center of the carbon atom to which X', Y' and Z' are attached, and is intended to represent both enantiomers in one figure. That is, a structural formula with such as a wavy bond denotes each of the enan ^ζ ' A thiomers separately, such as ^x ' ^γι or ^x A as well as their racemic mixture. When a wavy or curved bond is attached to a double bond moiety (such as C=C or C=N), it includes cis or trans (or E and Z-) geometric isomers or a mixture thereof.

It is to be understood herein that if a carbocyclic or heterocyclic moiety is bonded or otherwise attached to a designated substrate through various ring atoms without designating a specific point of attachment, then all possible points are contemplated, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term pyridyl means 2-, 3-, or 4-pyridyl, the term thienyl means 2- or 3-thienyl, and so on.

If a bond to a substituent is shown to cross a bond connecting two atoms in the ring, then such substituent may be bonded to any atom in the ring. If a substituent is indicated without specifying the atom by which such substituent is bonded to the remainder of the compound of a given formula, then such substituent may be bonded through any atom in that substituent. Combinations of substituents and/or variables are only allowed if such combinations result in stable compounds.

One skilled in the art will appreciate that substituents and other moieties of the compounds of the present invention must be chosen to provide a compound that is stable enough to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds of the present invention that exhibit such stability are considered to fall within the scope of the present invention.

The term counterion is used to represent negatively charged substances such as chloride, bromide, hydroxide, acetate, and sulfate. The term metal ion refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.

As used herein, the term substituted means that at least one hydrogen atom (attached to a carbon atom or heteroatom) is replaced by a non-hydrogen group, provided that the normal valency is maintained and that this substitution results in a stable compound. When the substituent is oxo (i.e. =O), then 2 hydrogen atoms are substituted on the atom. Oxo substituents are not present on aromatic moieties. When a ring system (eg, carbocyclic or heterocyclic) is indicated to be a substituted carbonyl group or double bond, the carbonyl group or double bond is assumed to be part of (ie, within) that ring. Circular double bonds in the context of this document are double bonds that are formed between two adjacent atoms of the ring group (for example, C=C, C=N or N=N). The term substituted with respect to alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl and heterocyclyl means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl and heterocyclyl, respectively , in which one or more hydrogen atoms that are attached to either a carbon or a heteroatom are each independently substituted with one or more non-hydrogen substituents.

In cases where nitrogen atoms (eg, amines) are present in the compounds of the present invention, they can be converted to N-oxides by treatment with an oxidizing agent (eg, mCPBA and/or hydrogen peroxides) to obtain other compounds of the present invention. Thus, the said and claimed nitrogen atoms are contemplated to encompass both said nitrogen and its derivative N-oxide (N^O).

When any variable occurs more than once in any constituent or compound formula, its definition in each instance is independent of its definition in every other instance. Thus, for example, if a group is substituted with 0, 1, 2, or 3 R groups as shown, then said group may be unsubstituted when it is substituted with 0 R groups, or may be substituted with up to three R groups, and in each case R independently selected from the definition for R.

In addition, combinations of substituents and/or variables are allowed only if such combinations lead to the formation of stable compounds.

As used herein, the term tautomer refers to any of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within a molecule. For example, one of skill in the art will readily appreciate that 1,2,3-triazole exists in two tautomeric forms as defined above:

[-N | 'N I NH

A N

Η

1//-1,2,3-triazole 2//-1,2,3-triazole

Thus, this disclosure is intended to cover all possible tautomers, even when the structure reflects only one of them.

The phrase pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions, and/or dosage forms that, on the basis of sound medical judgement, are acceptable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, and/or other problem. or complications commensurate with a reasonable benefit/risk ratio.

The compounds of the present invention may be present in the form of salts, which are also included in the scope of the present invention. Pharmaceutically acceptable salts are preferred. As used herein, the term pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by obtaining their acidic or basic salts. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic group using conventional chemical techniques. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or mixtures thereof; a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is generally preferred. For a list of suitable salts, see Remington's Pharmaceutical Sciences, ^18th Edition, Mack

- 15 042829

Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

If the compounds of the present invention have, for example, at least one basic center, they can form acid addition salts. They are formed, for example, with strong inorganic acids such as mineral acids, such as sulfuric acid, phosphoric acid or hydrohalic acid, with organic carboxylic acids, such as alkanecarboxylic acids containing 1 to 4 carbon atoms, such as acetic acid, which are unsubstituted or substituted, for example, with halogen, such as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, such as oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acids, such as hydroxycarboxylic acids, such as ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids (for example, aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (N-C/alkyl, or arylsulfonic acids, which are unsubstituted or substituted, for example, with halogen , for example methyl or p-toluenesulfonic acid. Also, if desired, the corresponding acid addition salts having an additionally present basic center can be formed. Compounds of the present invention having at least one acid group (eg COOH) may also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or ammonium or organic amine salts, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or a tri-lower alkylamine, eg ethyl, t-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, eg mono-, di- or triethanolamine. In addition, corresponding internal salts can be formed. Also included are salts which are not suitable for pharmaceutical applications, but which can be used, for example, to isolate or purify the free compounds of formula (I) or their pharmaceutically acceptable salts.

Preferred salts of compounds of formula (I) which contain a basic group include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, nitrate or acetate.

Preferred salts of compounds of formula (I) which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

In addition, the compounds of formula (I) may be in the form of prodrugs. Any compound that will be converted in vivo to produce a biologically active agent (ie, a compound of formula (I)) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such derivative prodrugs, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985) and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);

b) Bundgaard, H., Chapter 5, Design and Application of Prodrugs, A Textbook of Drug Design and Development, p. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. drug deliv. Rev. 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci. 77:285 (1988);

e) Kakeya, N. et al., Chem. Pharm. Bull. 32:692 (1984).

Compounds of the present invention containing a carboxy group can form physiologically hydrolysable esters which are used as prodrugs, i.e. prodrug esters, being hydrolysable in the body to form the compounds of the present invention per se. Examples of physiologically hydrolysable esters of the compounds of the present invention include (C1- _C6 )alkyl, (C1- _C6 )alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, _C1 . ₆ alkanoyloxy-C ₁ . ₆ alkyl (for example, acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), (C ₁ -C ₆ )alkoxycarbonyloxy (C ₁ -C ₆ )alkyl (for example, methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1, 3-dioxolen-4yl)methyl) and other well-known physiologically hydrolysable esters, used for example in the penicillin and cephalosporin fields. Such esters may be prepared using conventional techniques known in the art. Esters of prodrugs can be prepared by reacting the carboxylic acid moiety of the compounds of the present invention with an alkyl or aryl alcohol, halide, or sulfonate using techniques known to those skilled in the art. Such esters may be prepared by conventional methods known in the art.

The preparation of prodrugs is well known in the art and is described, for example, in King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999); Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

The present invention is intended to include all isotopes of atoms occurring in

- 16 042829 compounds according to the present invention. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The deuterium nucleus contains one proton and one neutron, and the mass of the nucleus is twice that of ordinary hydrogen. Deuterium may be represented by symbols such as ² H or D. The term deuterated herein, by itself or used to modify a compound or group, refers to the replacement of one or more hydrogen atoms that are attached to a carbon atom(s) with a deuterium atom . Isotopes of carbon include ¹³ C and ¹⁴ C.

Isotopically labeled compounds of the invention can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described herein, using an appropriate isotopically labeled reagent in place of the otherwise unlabeled reagent. Such compounds have many potential applications, for example, as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to target proteins or receptors, or to study the ability of compounds of the present invention to bind to biological receptors in vivo or in vitro.

The terms stable compound and stable structure are intended to indicate a compound that is sufficiently stable to withstand purification to an acceptable degree of purity from a reaction mixture and formulation into an effective therapeutic agent. Preferably, the compounds of the present invention do not contain an N-halogen, S(O) ₂ H or S(O)H group.

The term solvate means the physical association of a compound of the present invention with one or more solvent molecules, either organic or inorganic. This physical association provides for the formation of a hydrogen bond. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline solid. The solvent molecules in the solvate may be in a regular arrangement and/or a random arrangement. The solvent molecules in the solvate may be in a regular arrangement and/or a random arrangement. The solvate may include either a stoichiometric or non-stoichiometric amount of solvent molecules. The term solvate encompasses both the liquid phase and separable solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are generally known in the art.

Abbreviations.

The abbreviations used in this document are defined as follows: 1x once, 2x twice, 3x thrice, °C for degrees Celsius, equiv. for equivalent or equivalents, g for gram or grams, mg for milligram or milligrams, l for liter or liters, ml for milliliter or milliliters, µl for microliter or microliters, N for normality, M for molarity, mmol for millimoles or millimoles, min for minutes or minutes, h for hours or hours, rt for room temperature, RT for retention time, RBF for round bottom flask, atm for atmosphere, psi for psi, conc. for concentrated, RCM for metathesis cyclization, sat. or saturated for saturated, SFC for supercritical fluid chromatography, MW for molecular weight, mp for melting point, ee for enantiomeric excess, MS or Mass Spec for mass spectrometry, ESI for electrospray ionization, HR for high resolution, HRMS for mass spectrometry high resolution, LCMS for liquid chromatography with mass spectrometry, HPLC for high pressure liquid chromatography, RP HPLC for reverse phase HPLC, TLC or tlc for thin layer chromatography, NMR for nuclear magnetic resonance spectroscopy, nOe for nuclear Overhauser effect spectroscopy, 1H for proton, δ for delta, s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, br for wide, Hz for hertz, and α, β, R, S, E, and Z are stereochemical designations known to those skilled in the art.

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Me methyl Et ethyl Pr propyl z-Pr isopropyl Bu butyl z-Bu isobutyl 7-bu tert-butyl Ph phenyl bn benzyl Vos or VOS zzpezzz-butyloxycarbonyl WOSGO di-/7?/A/77-butyl dicarbonate AcOH or HO Ac acetic acid AICI3 aluminum trichloride AIBN azobis-isobutyronitrile VVgz boron tribromide BC1z boron trichloride BEMP 2-/7?/?s/7?-butyl imino-2-d iethylamino-1,3- dimethylperhydro-1,3,2-diazaphosphorine BON reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Burgess reagent 1-methoxy-M-triethylammoniosulfonyl- metanimidate CBz carbobenzyloxy DCM or CH2CI2 dichloromethane CH ₃ CN or ACN acetonitrile CDCI3 deutero-chloroform SNS1z chloroform shSRVA or sh-SRVA l/ethia-chloroperbenzoic acid CS2CO3 cesium carbonate Cu(OAc)2 copper(P) acetate

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Cy ₂ XMe DAST X-cyclohexyl-X-methylcyclohexanamine trifluoride (diethylamino) sulfur DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DEA diethylamine Dess-Martin reagent 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2benziod oxol-3-(1 H)-one DIC or DIPCDI diisopropylcarbodiimide DIEA, DIPEA or Hunig base diisopropylethylamine DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide cDNA complementary DNA Dppp DuPhos (A)-(+)-1,2-bis(diphenylphosphino)propane (+)-1,2-bis((28.58)-2,5-diethylphospholano)benzene EDC A-(3-dimethylaminopropyl)-A'-ethylcarbodiimide EDCI A-(3-dimethylaminopropyl)-X'-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid (S,S)-EtDuPhosRh(I) (+)-1,2-bis((28.58)-2,5-diethylphospholano)benzene- (1,5-cyclooctade yen)rhodium(1) trifluoromethane- sulfonate Et _3X or TEA triethylamine EtOAc ethyl acetate _Et2O diethyl ether EtOH ethanol GMF glass fiber filter Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium HCl hydrochloric acid HATU O-(7-azabenzotriazol-1-yl)-X,X,X',X'tetramethyluronium hexafluorophosphate

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HEPES 4-(2-hydroxyethyl)piperaxin-1-ethanesulfonic acid hex hexane HOBt or HOBT 1-hydroxybenzotriazole H2O2 hydrogen peroxide IBX 2-iodoxybenzoic acid H2SO4 sulfuric acid Jones reagent CrO3 in H2SO4 aqueous solution, 2M solution _{K2CO3 _} potassium carbonate K2HPO4 dibasic potassium phosphate (potassium hydrogen phosphate) KOAS potassium acetate KzRO ₄ tribasic potassium phosphate LAH lithium aluminum hydride LDA lithium diisopropylamide LG leaving group LiOH lithium hydroxide MeOH methanol _MgSO4 magnesium sulfate MsOH or MSA methyl sulfonic acid / methanesulfonic acid NaCl sodium chloride NaH sodium hydride _NaHCO3 bicarbonate of soda _{Na2CO3 _} sodium carbonate NaOH sodium hydroxide _{Na2SO3 _} sodium sulfite _{Na2SO4 _} sodium sulfate NBS N-bromosuccinimide NCS N-chlorosuccinimide _NH3 ammonia NH4CI ammonium chloride NH4OH ammonium hydroxide NH4 ⁺ _HCO2 ammonium formate NMM N-methylmorpholine OTf triflate or trifluoromethanesulfonate

- 20 042829

Pd ₂ (dba) ₃ tris(dibeisylideneacetone)dipalladium(0) Pd(OAc) ₂ palladium(P) acetate Pd/C palladium on coal Pd(dppf)C12 [1,G-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) Ph ₃ PCl ₂ triphenylphosphine dichloride PG protecting group POC1 ₃ phosphorus oxychloride PPTS pyridinium p-toluenesulfonate i-PrOH or IP A isopropanol PS polystyrene rt or rt room temperature SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride _SiO2 silicon oxide snch tin(P) chloride TBAF tetra-"-butylammonium fluoride TV AI tetra-n-butylammonium iodide TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyran TMSCHN2 trimethylsilyldiazomethane TMSCH ₂ N ₃ trimethylsilylmethylazide T3P propane-phosphonic acid anhydride TRIS tris(hydroxymethyl)aminomethane pTsOH p-toluenesulfonic acid

IV. Biology.

Lysophospholipids are bioactive lipid mediators of membrane origin. Lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxysn-glycero-3-phosphate; LPA), sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC). Lysophospholipids affect basic cellular functions, which include cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes, which include neurogenesis, angiogenesis, wound healing, immunity, and tumorigenesis.

Lysophosphatidic acid (LPA) acts through a number of specific G-protein coupled receptors (GPCRs) in an autocrine and paracrine manner. Binding of LPA to its cognate GPCRs (LPA1, LPA ₂ , LPA ₃ , LPA4, LPA5, LPA6) activates intracellular signaling pathways, providing a variety of biological responses.

Lysophospholipids such as LPA are quantitatively insignificant lipid species compared to their major phospholipid counterparts (eg phosphatidylcholine, phosphatidylethanolamine and sphingomyelin). LPA plays the role of a biological effector molecule and has a wide range of physiological actions such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, and a variety of cellular effects that include cell growth, cell rounding, axonal retraction, and actin formation. stress fibrils, and cell migration. The effects of LPA are predominantly receptor-mediated.

Activation of LPA receptors (LPA1, LPA2, LPA ₃ , LPA4, LPA5, LPA6) as a result of the action of LPA, in turn, triggers a number of downstream signaling cascades. These include, but are not limited to, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C (PLC) activation/Ca ²⁺ mobilization, arachidonic acid release, Akt/PKB activation, and activation of small GTPases, Rho, ROCK, Rac and Ras. Other pathways affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle protein 42/GTP-binding protein (Cdc42), proto-oncogene serine/threonine protein kinase Raf (c-RAF), tyrosine protein kinase Src proto-oncogene (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, lung myosin chain II (MLC II), nuclear factor kB (NF-kB), receptor activation

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N-methyl-D-aspartate (NMDA), phosphatidylinositol-3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), ras-related substrate 1 botulinum toxin C3 (RAC1). The specific signal transduction pathway and its final implementation depend on a number of variables, which include the receptor used, the cell type, the level of expression of the receptor or signaling protein, and the concentration of LPA. Nearly all mammalian cells, tissues, and organs co-express several subtypes of LPA receptors, indicating that LPA receptors are involved in signal transduction cooperatively. LPA1, LPA2 and LPA3 have high amino acid sequence similarity.

Lysophosphatidic acid (LPA) is released from activated platelets, activated adipocytes, neuronal cells and other cell types. Serum LPA is produced by a variety of enzymatic pathways that include monoacylglycerol kinase, phospholipase A1, secretory phospholipase A ₂ and lysophospholipase D (lysoPLD), including autotaxin. Several enzymes are involved in the degradation of LPA: lysophospholipase, lipid phosphate phosphatase, and an LPA acyltransferase such as endophilin. Human serum concentrations of LPA have been estimated to be 1-5 μM. Serum LPA is associated with albumin, low-density lipoproteins, or other proteins that may protect LPA from rapid degradation. There are naturally occurring molecular species of LPA with varying acyl chain lengths and saturations, including LPA 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1 ) 1-linoleoyl (18:2) and 1-arachidonyl (20:4). Quantitatively insignificant, alkyl-LPA has similar biological activity to acyl-LPA, and different LPA species activate LPA receptor subtypes with varying efficiencies.

LPA receptors.

LPA1 (formerly called VZG-1/EDG-2/mrec1.3) binds to three types of G proteins: G _i/o , G _q and G _12/13 . Through the activation of these G proteins, LPA induces a range of cellular responses via LPA1 including, but not limited to: cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C activation ( PLC), Ca ²⁺ mobilization, Akt activation, and Rho activation.

Extensive expression of LPA1 is observed in adult mice with a clear presence in the testicle, brain, heart, lung, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1; it is present in the brain, heart, lungs, placenta, colon, small intestine, prostate, testicle, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

LPA2 (EDG-4) also binds to three types of G proteins, G _i/o , G _q and G _12/13 to mediate LPA-induced cellular signaling. LPA2 expression is observed in the testes, kidneys, lungs, thymus, spleen, and stomach of adult mice, as well as in the testicles, pancreas, prostate, thymus, spleen, and human peripheral blood leukocytes. LPA2 expression is upregulated in various cancer cell lines, and several transcriptional variants of human LPA2 with mutations in the 3' untranslated region have been observed. Point deletion of LPA2 in mice did not show any overt phenotypic abnormalities, but showed a significant loss of normal LPA signaling (eg, PLC activation, Ca ²⁺ mobilization, and stress fiber formation) in mouse primary embryonic fibroblast (MEF) cultures. The creation of lpa1(-/-) lpa2(-/-) double null mice showed that many LPA-induced responses, which include cell proliferation, AC inhibition, PLC activation, Ca ²⁺ mobilization, JNK and Akt activation, and stress fiber formation , are absent or greatly reduced in double null-MEFs. All of these responses, with the exception of AC inhibition (AC inhibition is virtually abolished in LPA1 (-/-) MEF), are only partially affected in either LPA1 (-/-) or LPA2 (-/-) MEF. LPA2 promotes normal LPA-mediated signaling responses in at least some cell types (Choi et al., Biochemica et Biophysica Acta, 2008, 1781, p531-539).

LPA ₃ (EDG-7) differs from LPA1 and LPA2 in its ability to bind to G _i/o and G _q but not G _12/13 and is much less sensitive to LPA species with saturated acyl chains. LPA ₃ can mediate pleiotropic LPA-induced signaling, which includes PLC activation, Ca ²⁺ mobilization, AC inhibition/activation, and MAPK activation. Overexpression of LPA3 in neuroblastoma cells results in neurite elongation, while overexpression of LPA ₁ or LPA ₂ results in neurite retraction and cell rounding when stimulated with LPA. LPA ₃ expression is observed in the testis, kidney, lung, small intestine, heart, thymus, and brain of adult mice. In humans, expression is found in the heart, pancreas, prostate, testicle, lung, ovary, and brain (frontal cortex, hippocampus, and amygdala).

LPA4 (p2y9/GPR23) has a different sequence compared to LPA1, LPA2 and LPA3 with closer similarity to the platelet activating factor (PAF) receptor. LPA4 mediates LPA-induced Ca ²⁺ mobilization, cAMP accumulation, and functional binding to the G protein Gs to activate AS, as well as binding to other G proteins. The LPA4 gene is expressed in the ovary, pancreas, thymus, kidney, and skeletal muscle.

LPA ₅ (GPR92) is a member of the purinocluster GPCR and is structurally most closely related to LPA4.

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LPA5 is expressed in the human heart, placenta, spleen, brain, lungs, and intestines.

LPA5 also shows very high expression in the CD8+ lymphocyte compartment of the gastrointestinal tract.

LPA6 (p2y5) is a member of the GPCR purinocluster and is structurally most closely related to LPA ₄ . LPA6 is an LPA receptor associated with G12/13-Rho signaling pathways and is expressed in the inner root sheaths of human hair follicles.

Illustrative biological activity.

Wound healing.

Normal wound healing occurs through a highly coordinated sequence of events in which cellular, soluble factors, and matrix components work together to heal the injury. The healing response can be described as occurring in four broad intersecting phases: hemostasis, inflammation, proliferation, and remodeling. Many growth factors and cytokines are released at the wound site to initiate and promote wound healing processes.

When injured, damaged blood vessels activate platelets. Activated platelets play a key role in subsequent repair processes by releasing bioactive mediators to induce cell proliferation, cell migration, blood clotting and angiogenesis. LPA is one such mediator that is released from activated platelets; this causes platelet aggregation along with mitogenic/migratory effects on surrounding cells such as endothelial cells, smooth muscle cells, fibroblasts and keratinocytes.

Topical application of LPA to skin wounds in mice promotes repair processes (wound closure and increased neoepithelial thickness) by increasing cell proliferation/migration without causing secondary inflammation.

Activation of dermal fibroblasts by growth factors and cytokines leads to their subsequent migration from the wound edges into the temporary matrix formed by the fibrin clot, after which the fibroblasts proliferate and begin to repair the dermis, secreting and organizing the characteristic dermal extracellular matrix (ECM). The increasing number of fibroblasts in the wound and the continuous deposition of ECM increase matrix stiffness by applying small compressive forces to the newly formed granulation tissue. An increase in mechanical stress in combination with transforming growth factor β (TGFe) induces the expression of α-smooth muscle actin (α-SMA) and the subsequent transformation of fibroblasts into myofibroblasts. Myofibroblasts promote granulation tissue remodeling through myofibroblast contraction and production of ECM components.

LPA regulates many fibroblast functions important in wound healing, including proliferation, migration, differentiation, and contraction. Fibroblast proliferation in wound healing is required to fill an open wound. In contrast, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts, which actively synthesize ECM and pro-inflammatory cytokines. LPA can either increase or suppress the proliferation of various cell types that play an important role in wound healing, such as epithelial and endothelial cells (EC), macrophages, keratinocytes, and fibroblasts. The role of LPA1 in LPA-induced proliferation was revealed through the observation that LPA-stimulated proliferation of fibroblasts isolated from mice lacking the LPA1 receptor was attenuated (Mills et al., Nat. Rev. Cancer, 2003; 3:582-591) . LPA induces changes in the cytoskeleton that are integral to fibroblast adhesion, migration, differentiation, and contraction.

Fibrosis.

Tissue injury initiates a complex series of body responses to wound healing; if successful, such responses restore the structure and function of normal tissue. Otherwise, these responses can lead to tissue fibrosis and loss of function.

For most organs and tissues, the development of fibrosis involves many events and factors. Molecules involved in the development of fibrosis include proteins or peptides (profibrotic cytokines, chemokines, metalloproteinases, etc.) and phospholipids. Phospholipids involved in the development of fibrosis include platelet activating factor (PAF), phosphatidylcholine, sphingosine-1-phosphate (S1P), and lysophosphatidic acid (LPA).

Many muscular dystrophies are characterized by progressive muscle weakness and wasting, as well as extensive fibrosis. LPA treatment of cultured myoblasts has been shown to induce significant expression of connective tissue growth factor (CTGF). CTGF subsequently induces the expression of collagen, fibronectin, and integrin, and causes dedifferentiation of these myoblasts. LPA treatment of various cell types causes reproducible and high levels of CTGF induction (J.P. Pradere, et al., LPA1 receptor activation promotes renal interstitial fibrosis, J. Am. Soc. Nephrol. 18 (2007), 3110-3118; N. Wiedmaier , et al., Int. J. Med. Microbiol.; 298(3-4):23143, 2008). CTGF is a profibrotic cytokine that signals downstream and in parallel

- 23 042829 with TGFe.

The expression of CTGF by gingival epithelial cells, which are involved in the development of gingival fibromatosis, has been found to be aggravated by LPA treatment (A. Kantarci, et al., J. Pathol. 210 (2006), 59-66).

LPA is associated with the progression of liver fibrosis. In vitro, LPA induces proliferation of stellate cells and hepatocytes. These activated cells are the main cell type responsible for the accumulation of ECM in the liver. In addition, plasma LPA levels are increased during CCl4-induced liver fibrosis in rodents or hepatitis C virus-induced liver fibrosis in humans (N. Watanabe, et al., Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity, Life Sci 81 (2007), 1009-1015; N. Watanabe, et al., J. Clin Gastroenterol 41 (2007), 616-623.

An increase in phospholipid concentrations in lung lavage fluid as a biomarker for pulmonary fibrosis, Inhal. Toxicol. 18 (2006), 389-393 ; K. Yasuda, et al., Lung 172 (1994), 91-102).

LPA is associated with heart disease and myocardial remodeling. Serum levels of LPA increase after myocardial infarction in patients, and LPA stimulates rat heart fibroblast proliferation and collagen production (Chen et al. FEBS Lett. 2006 Aug 21; 580(19):4737-45).

Fibrosis of the lungs.

In the lungs, aberrant wound healing responses to injury contribute to the pathogenesis of fibrotic lung diseases. Fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) are associated with high morbidity and mortality.

LPA is an important mediator of fibroblast recruitment in pulmonary fibrosis. LPA and LPA1 play key pathogenetic roles in pulmonary fibrosis. The chemoattractant activity of fibroblasts plays an important role in the lungs of patients with pulmonary fibrosis. The profibrotic effects of LPA ₁ receptor stimulation are attributed to LPA ₁ receptor-mediated vascular leakage and increased fibroblast recruitment, both profibrotic events. The LPA-LPA1 pathway plays a role in mediated fibroblast migration and vascular leakage in the IPF. This eventually leads to the aberrant healing process that characterizes such a fibrotic state.

The LPA1 receptor is the LPA receptor most highly expressed on fibroblasts derived from IPF patients. In addition, bronchoalveolar lavage fluid (BAL) obtained from IPF patients induced chemotaxis in human fetal lung fibroblasts, which was blocked by the dual-acting LPA1-LPA3 receptor antagonist Ki16425. In an experimental mouse model of bleomycin-induced lung injury, LPA levels were shown to be high in bronchoalveolar lavage samples compared to untreated controls. LPA1 knockout mice are protected from fibrosis after bleomycin induction with reduced fibroblast accumulation and vascular leakage. In human subjects with IPF, high levels of LPA were observed in bronchoalveolar lavage samples compared to control samples obtained from healthy subjects. Increased fibroblast chemotactic activity in these samples was inhibited by Ki16425, indicating that fibroblast migration is mediated by the LPA receptor(s) of LPA (Tager et al. Nature Medicine, 2008, 14, 45-54).

The LPA-LPA1 pathway is critical for fibroblast recruitment and vascular leakage in pulmonary fibrosis.

Activation of latent TGFe by αΎβ6 integrin plays a critical role in the development of lung injury and fibrosis (Munger et al. Cell, vol. 96, 319-328, 1999). LPA induces αvβ6-mediated activation of TGFe on human lung epithelial cells (Xu et al. Am. J. Pathology, 2009, 174, 1264-1279). LPA-induced αve6-mediated activation of TGFe is mediated by the LPA ₂ receptor. LPA ₂ receptor expression is increased in epithelial cells and mesenchymal cells in areas of lung fibrosis in IPF patients compared to normal human lung tissue. The LPA-LPA2 pathway promotes activation of the TGFe pathway in pulmonary fibrosis. In some embodiments, compounds that inhibit LPA2 are effective in treating pulmonary fibrosis. In some embodiments, compounds that inhibit both LPA1 and LPA2 show improved efficacy in the treatment of pulmonary fibrosis compared to compounds that only inhibit LPA1 or LPA2.

The LPA1 antagonist BMS-986020 has been shown to significantly reduce FVC (forced vital capacity) in a 26-week clinical trial in patients with IPF (Palmer et al., Chest, 2018, 154, 1061-1069).

Fibrosis of the kidneys.

LPA and LPA1 are involved in the etiology of renal fibrosis. LPA influences both proliferation and contraction of glomerular mesangial cells and thus is involved in proliferative glomerulonephritis (C.N. Inoue, et al., Clin. Sci. (Colch.) 1999, 96, 431-436). On an animal model

- 24 042829 renal fibrosis [unilateral ureteral obstruction (UUO)] it was found that the renal LPA receptors are expressed in basal conditions with the order of expression LPA2>LPA ₃ = LPA ₁ >>LPA ₄ . This model rapidly mimics the development of renal fibrosis, including renal inflammation, fibroblast activation, and accumulation of extracellular matrix components in the glomeruli and interstitium. UUO significantly induced LPA ₁ receptor expression. This occurred in parallel with LPA production in the kidneys (3.3-fold increase) in the conditioned medium from kidney explants. Contrasting lateral kidneys showed no significant changes in LPA release and LPA receptor expression. This suggests that the precondition for LPA to act in fibrosis is met: production of a ligand (LPA) and induction of one of its receptors (LPA1 receptor) (JP Pradere et al., Biochimica et Biophysica Acta, 2008, 1781, 582-587) .

In LPA1 receptor (LPA1 (-/-) knockout mice, the development of renal fibrosis is significantly attenuated. UUO mice treated with the LPA receptor antagonist Ki16425 had a close similarity to the profile of LPA1 (-/-) mice.

LPA may be involved in intraperitoneal monocyte/macrophage accumulation, and LPA may induce expression of the profibrotic cytokine CTGF in primary cultures of human fibroblasts (J.S. Koh, et al., J. Clin. Invest., 1998, 102, 716-727).

LPA treatment of the mouse renal epithelial cell line, MCT, caused a rapid increase in the expression of the profibrotic cytokine CTGF. CTGF plays a critical role in UUO-induced tubulointerstitial fibrosis (TIF) and is involved in the profibrotic activity of TGFe. This induction was almost completely suppressed by co-treatment with the LPA receptor antagonist Ki16425. In one aspect, the profibrotic activity of LPA in the kidney results from the direct action of LPA on kidney cells, including the induction of CTGF.

Fibrosis of the liver.

LPA has been implicated in liver disease and fibrosis. Plasma levels of LPA and serum autotaxin (the enzyme responsible for LPA production) are elevated in patients with hepatitis and in animal models of liver injury in correlation with developing fibrosis. LPA also regulates the function of liver cells. LPA1 and LPA2 receptors are expressed by mouse liver stellate cells, and LPA stimulates the migration of liver myofibroblasts.

Fibrosis of the eye.

LPA is involved in the healing of eye wounds. LPA1 and LPA ₃ receptors are found in normal rabbit epithelial cells, keratocytes and endothelial cells, and LPA ₁ and LPA ₃ expression is increased in corneal epithelial cells after injury.

LPA and its homologues are present in intraocular and lacrimal fluid of the rabbit eye, and their levels are exceeded in the rabbit corneal injury model.

LPA induces the formation of actin stress fibers in endothelial and epithelial cells of the rabbit cornea and promotes contraction of fibroblasts in the cornea. LPA also stimulates the proliferation of pigmented human retinal epithelial cells.

fibrosis of the heart.

LPA has been implicated in myocardial infarction and cardiac fibrosis. Serum levels of LPA are elevated in post-myocardial infarction (MI) patients, and LPA stimulates proliferation and collagen production (fibrosis) by rat heart fibroblasts. Both LPA1 and LPA ₃ receptors are highly expressed in human cardiac tissue.

fibrosis treatment.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat or prevent fibrosis in a mammal. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat fibrosis of an organ or tissue in a mammal. In one aspect, a method is provided for preventing the onset of a fibrotic condition in a mammal, the method comprising administering to a mammal at risk of developing one or more fibrotic conditions, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of developing organ or tissue fibrosis. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of developing pulmonary, hepatic, or renal fibrosis. In one aspect, the mammal has a genetic predisposition to develop organ or tissue fibrosis. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a mammal to prevent or minimize post-injury scarring. In one aspect, the injury includes surgery.

The terms fibrosis or fibrotic disorder, as used herein, refer to conditions that are associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment, and include, but are not limited to, fibrosis of specific organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissues, peritoneal tissue, skin, cornea, retina, musculoskeletal system and gastrointestinal tract.

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Examples of diseases, disorders, or conditions in which fibrosis is involved include, but are not limited to, lung diseases associated with fibrosis, e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to a systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury, and acute respiratory distress (including those caused by bacterial pneumonia, trauma, viral pneumonia, ventilator, non-pulmonary sepsis and aspiration); chronic nephropathies associated with trauma/fibrosis (fibrosis of the kidneys), such as glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathy, hypertension, allograft and Alport syndrome; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis of the liver, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, virus-induced liver infection or fibrosis (eg, chronic hepatitis C), and autoimmune hepatitis; fibrosis of the head and neck, for example, caused by radiation; corneal scarring, eg LASIK (laser in situ keratomileusis), corneal transplant and trabeculectomy; hypertrophic scarring and keloids, such as those caused by burns or surgery; and other fibrotic diseases, for example, sarcoidosis, scleroderma, spinal cord injury/fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

In one aspect, a mammal suffering from one of the following non-limiting typical diseases, disorders or conditions would benefit from therapy with a compound of formula (I) or a pharmaceutically acceptable salt thereof: atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a mammal with organ or tissue fibrosis, or a predisposition to develop organ or tissue fibrosis, together with one or more other agents that are used to treat fibrosis. In one aspect, one or more agents include corticosteroids. In one aspect, one or more agents include immunosuppressants. In one aspect, one or more agents include B cell antagonists. In one aspect, one or more agents include uteroglobin.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat dermatological disorders in a mammal. As used herein, the term dermatological disorder refers to a skin disease. Such dermatological disorders include, but are not limited to, proliferative or inflammatory skin disorders such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring. , keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, urticaria. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat systemic sclerosis.

Pain.

Because LPA is released when tissue is damaged, LPA ₁ plays an important role in initiating neuropathic pain. LPA ₁ , unlike LPA2 or LPA ₃ , is expressed in both dorsal root ganglia (DRG) and dorsal root neurons. Using antisense oligodeoxynucleotide (AS-ODN) for LPAj and LPAi null mice, LPA-induced mechanical allodynia and hyperalgesia were found to be mediated by an LPA ₁ -dependent manner. LPA ₁ and downstream activation of Rho-ROCK play a role in initiating neuropathic pain signaling. Pretreatment with Clostridium botulinum exoenzyme C3 (BoTCS3, Rho inhibitor) or Y-27632 (ROCK inhibitor) completely abolished allodynia and hyperalgesia in mice with nerve injury. LPA also induced dorsal root demyelination, which was prevented by BoTCS3. Demyelination of the posterior root caused by trauma was not observed in LPA ₁ null mice or wild-type mice injected with AS-ODN. LPA signaling appears to induce important markers of neuropathic pain such as protein kinase Cy (PKCy) and the α2δ 1 subunit of voltage-gated calcium channels (Caα2δ1) in a LPA ₁ and Rho dependent manner (M. Inoue, et al., Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling, Nat Med 10 (2004), 712-718).

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat pain in a mammal. In one aspect, the pain is acute pain or chronic pain. In another aspect, the pain is neuropathic pain.

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In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of fibromyalgia. In one aspect, fibromyalgia is due to the formation of fibrous scar tissue in contractile (voluntary) muscles. Fibrosis binds tissues and inhibits blood flow, resulting in pain.

Cancer.

The lysophospholipid receptor signaling pathway plays a role in cancer etiology. Lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCR) LPA1, LPA2 and/or LPA3 are involved in the development of various types of cancer. Cancer initiation, progression, and metastasis involve several simultaneous and sequential processes, including cell proliferation and growth, survival and anti-apoptosis, cell migration, entry of foreign cells into certain cell layers and/or organs, and stimulation of angiogenesis. The control of each of these processes by LPA signaling under physiological and pathophysiological conditions highlights the potential therapeutic utility of modulating LPA signaling pathways for cancer treatment, especially at the level of LPA receptors or ATX/lysoPLD. Autotaxin (ATX) is a prometastatic enzyme originally isolated from the conditioned environment of human melanoma cells that stimulates a variety of biological activities including angiogenesis and promotion of cell growth, migration, survival and differentiation through LPA production (Mol. Cancer Ther., 2008; 7( 10):3352-62).

The LPA signals through its own GPCRs, resulting in the activation of multiple downstream effector pathways. Such downstream effector pathways play a role in cancer. LPA and its GPCR are associated with cancer through major oncogenic signaling pathways.

LPA promotes tumorigenesis by increasing cell motility and invasiveness. LPA is involved in the initiation or progression of ovarian cancer. LPA is present at significant concentrations (2-80 µM) in the ascitic fluid of patients with ovarian cancer. Ovarian cancer cells constitutively produce increased amounts of LPA compared to normal epithelial cells on the surface of the ovaries, precursors of epithelial ovarian cancer. Elevated levels of LPA are also found in plasma from patients with early stage ovarian cancer compared to controls. LPA receptors (LPA ₂ and LPA ₃ ) are also overexpressed in ovarian cancer cells compared to normal epithelial cells on the surface of the ovaries. LPA stimulates Cox-2 expression through transcriptional activation and post-transcriptional amplification of Cox-2 mRNA in ovarian cancer cells. Prostaglandins produced by Cox-2 are implicated in a number of human cancers, and pharmacological inhibition of Cox-2 activity reduces the development of colon cancer and reduces the size and number of adenomas in patients with familial adenomatous polyposis. LPA is also involved in the initiation or progression of prostate cancer, breast cancer, melanoma, head and neck cancer, colon (colorectal) cancer, thyroid cancer, and other cancers (Gardell et al., Trends in Molecular Medicine, vol. 12 , No. 2, pp. 65-75, 2006; Ishii et al., Annu. Rev. Biochem, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3, 582-591, 2003 ; Murph et al., Biochimica et Biophysica Acta, 1781, 547-557, 2008).

Cellular responses to LPA are mediated through lysophosphatidic acid receptors. For example, LPA receptors mediate both migration and invasion of pancreatic cancer cell lines: LPA1 and LPA ₃ antagonist (Ki16425) and LPA ₁ -specific siRNAs effectively blocked in vitro migration in response to LPA and peritoneal fluid (ascites) from patients with pancreatic cancer. glands; in addition, Ki16425 blocked the activity of LPA-induced and ascites-induced migration of strongly peritoneal metastases of a pancreatic cancer cell line (Yamada et al., J. Biol. Chem., 279, 6595-6605, 2004).

Colorectal carcinoma cell lines are characterized by a significant expression of LPA1 mRNA, and LPA induces the migration of these cells and the production of angiogenic factors. Overexpression of LPA receptors plays an important role in the pathogenesis of thyroid cancer. For the first time, LPA3 was cloned from prostate cancer cells, consistent with the ability of LPA to induce autocrine proliferation of prostate cancer cells.

LPA plays a stimulating role in the progression of many types of cancer. LPA is produced by prostate cancer cell lines and induces the proliferation of these cells. LPA induces, through the LPA ₁ signal transduction pathway, proliferation, migration, adhesion of human colon carcinoma cells of the DLD1 cell line, as well as the secretion of angiogenic factors by these cells. In other human colon carcinoma cell lines (HT29 and WiDR), LPA increases cell proliferation and secretion of angiogenic factors. In other colon cancer cell lines, activation of the LPA2 and _LPA3 receptors induces cell proliferation. Genetic or pharmacological manipulation of LPA metabolism, specific blockade of receptor signaling, and/or inhibition of downstream signaling pathways represent approaches to cancer therapy.

LPA and other phospholipids have been reported to stimulate interleukin-8 (IL-8) expression in ovarian cancer cell lines. In some embodiments, high concentrations of IL-8 in ovarian cancer correlate with a poor initial response to chemotherapy and a corresponding poor prognosis. In animal models, expression of IL-8 and other growth factors such as vascular endothelial growth factor (VEGF) is associated with increased tumorigenicity, ascites formation, angiogenesis, and invasiveness of ovarian cancer cells. In some aspects, IL-8 is an important modulator of cancer progression, drug resistance, and prognosis in ovarian cancer. In some embodiments, the compound of formula (I) inhibits or reduces the expression of IL-8 in ovarian cancer cell lines.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of cancer. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of a malignant and benign proliferative disease. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to prevent or reduce tumor cell proliferation, invasion, and metastasis of carcinomas, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma. , cancer pain, bone metastasis (Boucharaba et al., J. Clin. Invest., 2004, 114(12), 1714-1725; Boucharaba et al., Proc. Natl. Acad. Sci., 2006, 103(25) , 9643-9648). In one aspect, a method of treating cancer in a mammal is provided, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

As used herein, the term cancer refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, to metastasize (spread). Cancer types include, but are not limited to, solid tumors (such as solid tumors of the bladder, digestive tract, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organs ( thyroid), prostate, skin (melanoma or basal cell carcinoma), or hematologic tumors (such as leukemia) at any stage of the disease with or without metastases.

Additional non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumors, tumors of the brain and spinal cord, breast cancer, bronchial tumors, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonic tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST) ), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi's sarcoma , kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer , oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, low malignant potential ovarian tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, parenchymal tumors of the pineal gland glands of intermediate differentiation, pineoblastoma and supratentorial primary neuroectodermal tumors, pituitary tumor, plasma cell neoplasia/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (kidney), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family tumors, Kaposi's sarcoma, Cesari's syndrome, skin cancer, small cell lung cancer, small cell intestinal cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric), supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor.

Elevated concentrations of LPA and vesicles in ascites from ovarian cancer patients and in breast cancer effusions indicate that it may be an early diagnostic marker, prognostic indicator, or indicator of response to therapy (Mills et al., Nat. Rev. Cancer., 3 , 582-591, 2003;

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Sutphen et al., Cancer Epidemiol. Biomarkers Prev. 13, 1185-1191, 2004). LPA concentrations are consistently higher in ascites samples than in corresponding plasma samples.

Respiratory and allergic disorders.

In one aspect, LPA contributes to the pathogenesis of respiratory diseases. In one aspect, the respiratory disease is asthma. The pro-inflammatory effects of LPA include mast cell degranulation, smooth muscle cell contraction, and cytokine release from dendritic cells. Airway smooth muscle cells, epithelial cells, and lung fibroblasts all show responses to LPA. LPA induces the secretion of IL-8 by human bronchial epithelial cells. IL-8 is found at elevated concentrations in the BAL fluids of patients with asthma, chronic obstructive pulmonary disease, pulmonary sarcoidosis, and acute respiratory distress syndrome, and I1-8 has been shown to exacerbate airway inflammation and airway remodeling in asthmatics. All LPA1, LPA ₂ and LPA ₃ receptors have been shown to contribute to LPA-induced IL-8 production. Studies cloning multiple GPCRs that are activated by LPA have demonstrated the presence of mRNA for LPA1, LPA2 and LPA ₃ in the lungs (JJA Contos, et al., Mol. Pharmacol. 58, 1188-1196, 2000).

The release of LPA from platelets activated at the site of injury and its ability to stimulate fibroblast proliferation and contraction are features of LPA as a mediator of wound healing. In the context of airway disease, asthma is an inflammatory disease in which improper airway repair processes lead to structural remodeling of the airways. In asthma, airway cells are subjected to constant injury from a variety of influences, including allergens, pollutants, other inhaled environmental substances, bacteria, and viruses, leading to the chronic inflammation that is characteristic of asthma.

In one aspect, in an individual with asthma, the release of normal recovery mediators, including LPA, is abnormally increased or the actions of recovery mediators are inappropriately prolonged, resulting in inadequate airway remodeling. The main structural features of the remodeled airways seen in asthma include a thickened lamina reticularis (basal membrane-like structure just below the epithelial cells of the airways), increased numbers and activation of myofibroblasts, thickening of the smooth muscle layer, increased mucus glands, and mucus secretion. and changes in connective tissue and capillary bed throughout the airway wall. In one aspect, LPA promotes these structural changes in the airways. In one aspect, LPA is involved in acute airway hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airway is narrower due to thickening of the airway wall, thereby reducing airflow. In one aspect, LPA promotes long-term structural remodeling and acute asthmatic airway hyperresponsiveness. In one aspect, LPA promotes hyperresponsiveness, which is a major feature of acute asthma exacerbations.

In addition to LPA-mediated cellular responses, several components of the LPA signaling pathway leading to these responses are relevant to asthma. Upregulation of the EGF receptor is induced by LPA and has also been observed in asthmatic airways (M. Amishima, et al., Am. J. Respir. Crit. Care Med. 157, 1907-1912, 1998). Chronic inflammation contributes to asthma, and several transcription factors that are activated by LPA are known to be involved in inflammation (Ediger et al., Eur. Respir. J. 21:759-769, 2003).

In one aspect, fibroblast proliferation and contraction and extracellular matrix secretion stimulated by LPA contribute to the fibroproliferative features of other airway diseases such as peribronchiolar fibrosis present in chronic bronchitis, emphysema, and interstitial lung disease. Emphysema is also associated with mild fibrosis of the alveolar wall, a feature thought to represent an attempt to repair alveolar damage. In another aspect, LPA plays a role in fibrotic interstitial lung disease and bronchiolitis obliterans where both collagen and myofibroblasts are elevated. In another aspect, LPA is involved in several of the various syndromes that are chronic obstructive pulmonary disease.

In vivo administration of LPA causes airway hypersensitivity, scratching in response to itching, eosinophil and neutrophil infiltration and activation, vascular remodeling, and nociceptive flexor responses. LPA also induces histamine release in mouse and rat mast cells. In an acute allergic reaction, histamine causes various reactions such as smooth muscle contraction, plasma exudation, and mucus production. Plasma exudation is important in the airways because leakage and subsequent swelling of the airway wall contribute to the development of airway hypersensitivity. Plasma exudation progresses to conjunctival edema in allergic ocular disorder and nasal congestion in allergic rhinitis (Hashimoto et al., J. Pharmacol. Sci. 100, 82-87, 2006). In one aspect, LPA-induced plasma exudation is mediated by histamine release from mast cells via one or more LPA receptors. In one aspect, the LPA receptor(s) include LPA ₁ and/or LPA3. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of various allergic diseases in mammals. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of respiratory diseases, disorders, or conditions in a mammal. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of asthma in a mammal. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of chronic asthma in a mammal.

As used herein, the term respiratory disease refers to diseases of the organs that are involved in breathing, such as the nose, throat, larynx, Eustachian tubes, trachea, bronchi, lungs, associated muscles (eg, diaphragm and intercostal bones), and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-responsive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation, and cystic fibrosis and hypoxia.

As used herein, the term asthma refers to any lung disorder characterized by changes in pulmonary gas flow associated with airway constriction from any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma can be used with one or more adjectives to indicate the cause.

In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of chronic obstructive pulmonary disease in a mammal, comprising administering to the mammal at least once an effective amount of at least one compound of formula (I), or its pharmaceutically acceptable salt. In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, and/or airway inflammation, and cystic fibrosis.

Nervous system.

The nervous system is the main locus for the expression of LPA ₁ ; there it is spatially and temporally regulated throughout brain development. Oligodendrocytes, myelinating cells in the central nervous system (CNS), express LPA ₁ in mammals. In addition, Schwann cells, myelinating cells of the peripheral nervous system, also express LPAj, which is involved in the regulation of Schwann cell survival and morphology. These observations define important functions for LPA receptor-mediated signaling in neurogenesis, cell survival, and myelination.

Exposure of peripheral nervous system cell lines to LPA results in rapid retraction of their processes resulting in cell rounding, which is mediated in part by polymerization of the actin cytoskeleton. In one aspect, LPA induces neuronal degeneration under pathological conditions where the blood-brain barrier is damaged and serum components enter the brain (Moolenaar, Curr. Opin. Cell Biol. 7:203-10, 1995). Immortalized CNS neuroblast cell lines from the cerebral cortex also demonstrate retraction responses to LPA exposure via Rho activation and actomyosin interactions. In one aspect, LPA is associated with postischemic neuronal injury (J. Neurochem. 61, 340, 1993; J. Neurochem., 70:66, 1998).

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment or prevention of a nervous system disorder in a mammal. The term nervous system disorder as used herein refers to conditions that alter the structure or function of the brain, spinal cord, or peripheral nervous system, including, but not limited to, Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathies, Parkinson's disease, conditions following blunt or surgical trauma (including postoperative cognitive dysfunction and damage to the spinal cord or brainstem), and neurological aspects of disorders such as degenerative spinal disease and sciatica.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment or prevention of a CNS disorder in a mammal. CNS disorders include, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, postoperative cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema

- 30 042829 brain and head injury.

Cardiovascular disorders.

Cardiovascular phenotypes observed after targeted deletion of lysophospholipid receptors show an important role for lysophospholipid signaling in blood vessel development and maturation, atherosclerotic plaque formation, and heart rhythm maintenance (Ishii, I. et al., Annu. Rev. Biochem. 73, 321 -354, 2004). Angiogenesis, the formation of new capillary networks from an already existing vascular system, is normally triggered by wound healing, tissue growth, and myocardial angiogenesis after ischemic injury. Peptide growth factors (eg, vascular endothelial growth factor (VEGF)) and lysophospholipids control the coordinated proliferation, migration, adhesion, differentiation, and assembly of vascular endothelial cells (VECs) and surrounding vascular smooth muscle cells (VSMCs). In one aspect, dysregulation of angiogenesis-mediating processes leads to the development of atherosclerosis, hypertension, tumor growth, rheumatoid arthritis, and diabetic retinopathy (Osborne, N. and Stainier, D.Y. Annu. Rev. Physiol. 65, 23-43, 2003).

Downstream signaling pathways mediated by lysophospholipid receptors include Rac-dependent lamellopodia formation (eg, LPA1) and Rho-dependent stress fiber formation (eg, LPA1), which are important for cell migration and adhesion. Vascular endothelial dysfunction can shift the balance from vasodilation to vasoconstriction and lead to hypertension and vascular remodeling, which are risk factors for atherosclerosis (Maguire, J. J. et al., Trends Pharmacol. Sci. 26, 448-454, 2005).

LPA contributes to both the early phase (barrier dysfunction and endothelial monocyte adhesion) and late phase (platelet activation and intra-arterial thrombus formation) of atherosclerosis, in addition to its overall progression. At an early stage, LPA from multiple sources accumulates in lesions and activates related GPCRs (LPA1 and LPA3) expressed on platelets (Siess, W. Biochim. Biophys. Acta 1582, 204-215, 2002; Rother, E. et al. Circulation, 108, 741747, 2003). This causes platelet reshaping and aggregation, leading to intra-arterial thrombus formation and possibly myocardial infarction and stroke. In support of its atherogenic activity, LPA can also be a mitogen and motogen for VSMCs and an activator of endothelial cells and macrophages. In one aspect, mammals with cardiovascular disease benefit from LPA receptor antagonists that prevent thrombus and neointima plaque formation.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat or prevent cardiovascular disease in a mammal.

As used herein, the term cardiovascular disease refers to diseases affecting the heart or blood vessels, or both, including, but not limited to: arrhythmias (atrial or ventricular, or both); atherosclerosis and its complications; angina; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, or other organ or tissue; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular disorders, inflammation, insufficiency, limited to one organ or tissue.

In one aspect, provided herein are methods for preventing or treating vasoconstriction, atherosclerosis and its complications, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, comprising administering to a mammal at least once an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or a medicament which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are methods of reducing reperfusion injury to the heart following myocardial ischemia and/or endotoxic shock, comprising at least once administering to a mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are methods of reducing vasoconstriction in a mammal, comprising at least once administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are methods for reducing or preventing an increase in blood pressure in a mammal, comprising at least once administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

Inflammation.

LPA has been shown to regulate immunological responses by modulating actively

- 31 042829 sti/functions of immune cells such as T-/B-lymphocytes and macrophages. In activated T cells, LPA activates IL-2 production/cell proliferation via LPA1 (Gardell et al., TRENDS in Molecular Medicine Vol. 12 No. 2 February 2006). Expression of LPA-induced inflammatory response genes is mediated by LPA1 and LPA ₃ (Biochem Biophys Res Commun. 363(4): 1001-8, 2007). In addition, LPA modulates inflammatory cell chemotaxis (Biochem Biophys Res Commun., 1993, 15; 193(2), 497). Proliferative and cytokine-secreting activity in response to LPA of immune cells (J. Imuunol. 1999, 162, 2049), platelet aggregation activity in response to LPA, acceleration of migration activity in monocytes, activation of NF-κB in fibroblasts, increased binding of fibronectin to cell surface, etc. are famous. Thus, LPA is associated with various inflammatory/immune diseases.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to treat or prevent inflammation in a mammal. In one aspect, LPA1 and/or LPA ₃ antagonists find use in the treatment or prevention of inflammatory/immune disorders in a mammal. In one aspect, the LPA1 antagonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Examples of inflammatory/immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic (organ, bone marrow, stem cell) transplantation. cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis (eg, Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.

Other diseases, disorders or conditions.

In accordance with one aspect, methods are provided for treating, preventing, reversing the trend, stopping or slowing the progression of clinically significant LPA-dependent or LPA-mediated diseases or conditions, or treating symptoms associated with or associated with LPA-dependent or LPA-mediated diseases or conditions, by administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject already has an LPA-dependent or LPA-mediated disease or condition at the time of administration, or is at risk of developing an LPA-dependent or LPA-mediated disease or condition.

In some aspects, LPA1 activity in a mammal is directly or indirectly modulated by administration (at least once) of a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof. Such modulation includes, but is not limited to, reduction and/or inhibition of LPA1 activity. In additional aspects, LPA activity in a mammal is directly or indirectly modulated, including reduction and/or inhibition, by administration (at least once) of a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof. Such modulation includes, but is not limited to, reducing and/or inhibiting the amount and/or activity of the LPA receptor. In one aspect, the LPA receptor is LPA1.

In one aspect, LPA has a contracting effect on bladder smooth muscle cells isolated from the bladder and promotes the growth of prostate-derived epithelial cells (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000, 163, 1027 -1032). In another aspect, LPA compresses the urinary tract and prostate in vitro and increases intraurethral pressure in vivo (WO 02/062389).

In some aspects, methods are provided for preventing or treating the recruitment of eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or monocytes and/or T cells, comprising at least once administering to a mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some aspects, methods for treating cystitis, including, for example, interstitial cystitis, are provided, comprising at least once administering to a mammal a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one aspect, the methods described herein include diagnosing or determining whether or not a patient has an LPA-dependent or LPA-mediated disease or condition by administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically effective amount thereof. acceptable salt and determining whether or not there is a positive result in response to this treatment.

In one aspect, provided herein are compounds of formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable

- 32 042829 solvates that are LPA1 antagonists and are used to treat patients suffering from one or more LPA-dependent or LPA-mediated conditions or diseases, including, but not limited to, pulmonary fibrosis, kidney fibrosis, liver fibrosis, scarring, asthma, rhinitis , chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, arthritis, allergies, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders, and inflammatory conditions. In some embodiments, LPA-dependent conditions or diseases include conditions or diseases in which an absolute or relative excess of LPA is present and/or observed.

In any of the above aspects, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ fibrosis, asthma, allergic disorders, chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary or pleural fibrosis, peritoneal fibrosis, arthritis, allergies, cancer. , cardiovascular disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used to improve corneal desensitization resulting from corneal surgery such as laser in situ keratomileusis (LASIK) or cataract removal, to improve corneal desensitization resulting from corneal degeneration, and for the treatment of dry eye symptom caused by the same causes.

In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment or prevention of inflammatory eye disease and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis in a mammal, comprising at least once administering to the mammal an effective amount of at least one a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment or prevention of Sjögren's disease or an inflammatory disease associated with dry eye in a mammal, comprising at least once administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, LPA and LPA receptors (eg, LPA1) are involved in the pathogenesis of osteoarthritis (Kotani et al., Hum. Mol. Genet., 2008, 17, 1790-1797). In one aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of osteoarthritis in a mammal, comprising at least once administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, LPA receptors (eg, LPA1, LPA3) contribute to the pathogenesis of rheumatoid arthritis (Zhao et al., Mol. Pharmacol., 2008, 73(2), 587-600). In one aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of rheumatoid arthritis in a mammal, comprising at least once administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof. .

In one aspect, LPA receptors (eg, LPA1) contribute to lipogenesis. (Simon et al., J. Biol. Chem., 2005, vol. 280, no. 15, p. 14656). In one aspect, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for promoting adipose tissue formation in a mammal, comprising at least once administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.

(a) In vitro assays.

The effectiveness of the compounds of the present invention as inhibitors of LPA1 can be determined in the functional analysis of the LPA ₁ antagonist as follows.

Chinese hamster ovary cells overexpressing human LPA1 were plated overnight (15,000 cells/well) in polyU-lysine coated 384-well microplates (Greiner bio-one, cat. no. 781946) in DMEM/F12 medium (Gibco, cat. no. 11039). ). After culturing overnight, cells were loaded with calcium indicator dye (Bioquest Inc. AAT, catalog number 34601) for 30 minutes at 37°C. The cells were then equilibrated to room temperature for 30 min prior to analysis. Test compounds solubilized in DMSO were transferred to 384-well non-binding surface plates (Corning, cat. no. 3575) using a Labcyte Echo acoustic dispenser station and diluted with assay buffer [1X HBSS with calcium/magnesium (Gibco, cat. no. 14025 -092), 20 mM HEPES (Gibco, cat. no. 15630-080), and 0.1% fatty acid-free BSA (Sigma, cat. no. A9205)] to a final concentration of 0.5% DMSO. Diluted compounds were added to cells with

- 33 042829

FDSS6000 (Hamamatsu) at final concentrations ranging from 0.08 nM to 5 μM and then incubated for 20 min at room temperature, after which LPA (Avanti Polar Lipids, cat. no. 857130C) was added at final concentrations of 10 nM to stimulate cells . The IC ₅₀ value for a compound was defined as the concentration of test compound that inhibited 50% of the calcium flux induced by LPA alone. IC ₅₀ values were determined by fitting the data to a 4-parameter logistic equation (GraphPad Prism, San Diego CA).

(b) In vivo assays.

Test with LPA with an assessment of the concentration of histamine in plasma.

The compound was administered orally, po, to female CD-1 mice 2 hours prior to LPA challenge. Mice were then injected via the tail vein (IV) with 0.15 ml LPA in 0.1% BSA/PBS (2 μg/μl). Exactly 2 min after LPA administration, mice were sacrificed by decapitation and trunk blood was collected. These samples were co-centrifuged and individual 75 μl samples were frozen at -20° C. prior to analysis for histamine.

Analysis of histamine in plasma was performed by the standard method of EIA (enzymatic immunoassay). Plasma samples were thawed and diluted 1:30 in 0.1% BSA in PBS. The EIA protocol for histamine assay described by the manufacturer (Histamine EIA, Oxford Biomedical Research, EA#31) was followed.

The LPA used in the assay was formulated as follows: LPA (1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P, Avanti Polar Lipids) was prepared in 0.1% BSA/PBS at a total concentration of 2 µg/µl . Weighed 13 mg LPA and added 6.5 ml 0.1% BSA, vortexed and sonicated for ~1 h until a clear solution was obtained.

V. Pharmaceutical compositions, formulations and combinations.

In some embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the implementation of the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient.

In some embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In one aspect, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ophthalmic or otic administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drops, or ear drops. .

In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutically active agents selected from: corticosteroids (eg, dexamethasone or fluticasone), immunosuppressants (eg, tacrolimus and pimecrolimus), analgesics, anti-cancer agent, anti-inflammatory drugs, receptor antagonists chemokine, bronchodilators, leukotriene receptor antagonists (e.g. montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A ₂ inhibitors and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, anticongestants, antihistamines (e.g. loratidine), mucolytics, anticholinergics, antitussives, expectorants, anti-infectives (eg, fusidic acid, in particular for the treatment of atopic dermatitis), antifungals (eg, clotriasol, in particular for the treatment of atopic dermatitis), anti-IgE antibody therapy ( omalizumab), β-2 adrenergic agonists (eg albuterol or salmeterol), other PGD2 antagonists acting on other receptors such as DP antagonists, PDE4 inhibitors (eg cilomilast), drugs that modulate cytokine production, eg inhibitors TACE, drugs that modulate the activity of the Th2 cytokines IL-4 and IL-5 (eg, blocking monoclonal antibodies and soluble receptors), PPARy agonists (eg, rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (eg, zileuton).

In some embodiments, the pharmaceutical composition further comprises one or more additional anti-fibrotic agents selected from pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alfa, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM- 152, IFN-gamma-1b, IW-001, PRM-151, PXS-25, pentoxifylline/K-acetylcysteine, pentoxifylline/vitamin E, salbutamol sulfate, [Sar9,Met(O2)11]-substance P, pentoxifylline, bitartrate mercaptamine, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acid ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151. In some embodiments, a method is provided comprising administering a compound of formula (I) or pharmaceutically thereof

- 34 042829 acceptable salt to a person with an LPA-dependent or LPA-mediated disease or condition. In some embodiments, the human is already being administered one or more additional therapeutically active agents other than the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more additional therapeutically active agents, other than a compound of formula (I) or a pharmaceutically acceptable salt thereof, is selected from: corticosteroids (eg, dexamethasone or fluticasone), immunosuppressants (eg, tacrolimus and pimecrolimus), analgesics, anticancer agents , anti-inflammatory agents, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (eg montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A ₁ inhibitors, phospholipase A2 inhibitors and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, anticongestants, antihistamines (eg, loratidine), mucolytics, anticholinergics, antitussives, expectorants, anti-infectives (eg, fusidic acid, in particular for the treatment of atopic dermatitis), antifungals (eg, clotriasol, in particular for the treatment of atopic dermatitis) anti-IgE antibody therapies (eg omalizumab), β-2 adrenergic agonists (eg albuterol or salmeterol), other PGD2 antagonists acting on other receptors such as DP antagonists, PDE4 inhibitors (eg cilomilast), drugs that modulate cytokine production, such as TACE inhibitors, drugs that modulate the activity of the Th2 cytokines IL-4 and IL-5 (eg, blocking monoclonal antibodies and soluble receptors), PPARy agonists (eg, rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors ( e.g. zileuton).

In some embodiments, one or more additional therapeutically active agents, other than a compound of formula (I) or a pharmaceutically acceptable salt thereof, are other antifibrotic agents selected from pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alfa, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25, pentoxifylline/N-acetylcysteine, pentoxifylline/vitamin E, salbutamol sulfate, [Sar9, Met(O2)11]-substance P, pentoxifylline, mercaptamine bitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acid ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX -102, RO-5093151.

In some embodiments, one or more additional therapeutically active agents, other than a compound of formula (I) or a pharmaceutically acceptable salt thereof, is selected from ACE inhibitors, ramipril, AII antagonists, irbesartan, antiarrhythmic agents, dronedarone, PPARa activators, PPARy activators, pioglitazone , rosiglitazone, prostanoids, endothelin receptor antagonists, elastase inhibitors, calcium antagonists, beta-blockers, diuretics, aldosterone receptor antagonists, eplerenone, renin inhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, PDE inhibitors, PDE5 inhibitors, NO donors, digitalis, ACE/NEP inhibitors, statins, bile acid reuptake inhibitors, PDGF antagonists, vasopressin antagonists, aquaretics, NHE1 inhibitors, factor Xa antagonists, factor XIIIa antagonists, anticoagulants, antithrombotic agents, platelet inhibitors, profibrotic agents, activated fibrinolysis inhibitors (TAFIs), PAI-1 inhibitors, coumarins, heparins, thromboxane antagonists, serotonin antagonists, COX inhibitors, aspirin, therapeutic antibodies, GPIIb/IIIa antagonists, ER antagonists, SERMs, tyrosine kinase inhibitors, RAF kinase inhibitors, p38 inhibitors MAPK, pirfenidone, multikinase inhibitors, nintedanib, sorafenib.

In some embodiments, one or more additional therapeutically active agents, other than a compound of formula (I) or a pharmaceutically acceptable salt thereof, is selected from Gremlin-1 mAb, PAI-1 mAb, Promedior (PRM-151; recombinant human Pentraxin-2); FGF21, TGFe antagonists, ανβ6 and ανβ pan-antagonists; FAK inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120.

The pharmaceutical formulations described herein may be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, low melting formulations, tablets, capsules, pills, sustained release formulations, extended release formulations

- 35 042829 release, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically. In such embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is formulated in various topical formulations such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubbings, lubricants, medicated sticks, medicated dressings, balms. , creams or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity agents, buffers and preservatives. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically to the skin.

In yet another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered by inhalation. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered by inhalation, which directly affects the pulmonary system.

In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

In another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is formulated as eye drops.

In yet another aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided in the manufacture of a medicament for the treatment of a disease, disorder or conditions in which the activity of at least one LPA receptor contributes to the pathology and/or symptoms of the disease or condition. In one embodiment of this aspect, the LPA is selected from LPAj, LPA2, LPA ₃ , LPA4, LPA ₅ and LPA6. In one aspect, the LPA receptor is LPAj. In one aspect, the disease or condition is any of the diseases or conditions identified herein.

In any of the above aspects, further embodiments are contemplated, wherein (a) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is systemically administered to a mammal; and/or (b) an effective amount of the compound is orally administered to the mammal; and/or (c) an effective amount of the compound is administered intravenously to the mammal; and/or (d) an effective amount of the compound is administered via inhalation; and/or (e) an effective amount of the compound is administered via nasal administration; and/or (f) an effective amount of the compound is administered to the mammal by injection; and/or (g) an effective amount of the compound is administered topically to the mammal; and/or (h) an effective amount of the compound is administered to the eye; and/or (i) an effective amount of the compound is administered rectally to the mammal; and/or (j) an effective amount is administered to the mammal non-systemically or locally.

In any of the above aspects, further embodiments are contemplated, comprising a single administration of an effective amount of a compound, including other embodiments wherein (i) the compound is administered once; (ii) the compound is administered to the mammal several times over the course of one day; (iii) permanently; or (iv) continuously.

In any of the above aspects, further embodiments are contemplated, comprising multiple administrations of an effective amount of a compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple injections is 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday in which administration of the compound is temporarily suspended or doses of the administered compound are temporarily reduced; and at the end of the drug holiday, the dosage of the compound is reinstated. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

Also provided is a method for inhibiting the physiological activity of LPA in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

In one aspect, a medicament for the treatment of an LPA-dependent or LPA-mediated disease or condition in a mammal is provided, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some instances, this document discloses the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an LPA-dependent or LPA-mediated disease or condition.

In some instances, this document discloses the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the treatment or prevention of an LPA-dependent or LPA-mediated disease or condition.

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In one aspect, a method is provided for treating or preventing LPA-dependent or

An LPA-mediated disease or condition in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one aspect, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ or tissue fibrosis, scarring, liver diseases, dermatological conditions, cancer, cardiovascular disease, diseases or conditions of the respiratory system, inflammatory diseases, disease gastrointestinal tract, kidney disease, urinary tract disease, inflammatory disease of the lower urinary tract, dysuria, urinary frequency, pancreatic disease, arterial obstruction, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy and fibromyalgia.

In one aspect, the LPA-dependent or LPA-mediated disease or condition is a disease or condition of the organs of the respiratory system. In some embodiments, the disease or condition of the respiratory system is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary arterial hypertension, or acute respiratory distress syndrome.

In some embodiments, the LPA-dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; other diffuse diseases of the lung parenchyma of various etiologies, including iatrogenic drug-induced fibrosis, occupational and/or environmental fibrosis, granulomatous diseases (sarcoidosis, allergic alveolitis), collagen vascular diseases, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, hereditary diseases ( Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic disorders, familial interstitial lung disease); radiation-induced fibrosis; chronic obstructive pulmonary disease (COPD); scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); fibrosis of the kidneys; tubulointerstitial fibrosis; glomerular nephritis; focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport syndrome; intestinal fibrosis; liver fibrosis; cirrhosis of the liver; alcohol-induced liver fibrosis; toxic/drug-induced liver fibrosis; hemochromatosis; non-alcoholic steatohepatitis (NASH); damage to the bile ducts; primary biliary cirrhosis; infection-induced liver fibrosis; virus-induced liver fibrosis; and autoimmune hepatitis; scarring of the cornea; hypertrophic scarring; Dupuytren's disease, keloids, skin fibrosis; skin scleroderma; spinal cord injury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chronic lymphocytic leukemia, tumor metastasis, transplant organ rejection, endometriosis, neonatal respiratory distress syndrome, and neuropathic pain.

In one aspect, an LPA-dependent or LPA-mediated disease or condition is described herein.

In one aspect, there is provided a method for treating or preventing organ fibrosis in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

In one aspect, organ fibrosis includes pulmonary fibrosis, renal fibrosis, or hepatic fibrosis.

In one aspect, a method for improving lung function in a mammal is provided, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a mammal in need thereof. In one aspect, the mammal has been diagnosed with pulmonary fibrosis.

In one aspect, the compounds disclosed herein are used to treat idiopathic pulmonary fibrosis (usually interstitial pneumonia) in a mammal.

In some embodiments, the compounds disclosed herein are used to treat diffuse parenchymal interstitial lung diseases in mammals: iatrogenic drug-induced fibrosis, occupational and/or environmentally induced fibrosis (allergic alveolitis in agricultural workers), granulomatous diseases (sarcoidosis, allergic alveolitis), collagen vascular diseases (scleroderma and others), alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic disorders, familial interstitial lung disease.

In some embodiments, the compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: bronchiolitis obliterans after lung transplantation.

In some embodiments, the compounds disclosed herein are used to treat cutaneous fibrosis in a mammal: cutaneous scleroderma, Dupuytren's disease, keloids.

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In one aspect, the compounds disclosed herein are used to treat liver fibrosis with or without cirrhosis in a mammal: toxic substance/drug induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV) , non-alcoholic liver disease (NAFLD, NASH), metabolic disorders and autoimmune disease.

In one aspect, the compounds disclosed herein are used to treat renal fibrosis in a mammal: tubulointerstitial fibrosis, glomerular sclerosis.

In any of the above aspects involving the treatment of LPA-dependent diseases or conditions, further embodiments are contemplated, comprising administering at least one additional agent in addition to administering a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. In various embodiments, each agent is administered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, the compounds provided herein are administered to a human.

In some embodiments, the compounds provided herein are administered orally.

In some embodiments, the compounds provided herein are used as antagonists of at least one LPA receptor. In some embodiments, the compounds provided herein are used to inhibit the activity of at least one LPA receptor, or to treat a disease or condition that would benefit from inhibiting the activity of at least one LPA receptor. In one aspect, the LPA receptor is LPA1.

In other embodiments, the compounds provided herein are used to formulate a medicament for inhibiting LPA1 activity.

Finished articles are provided that include a packaging material, a compound of formula (I) or a pharmaceutically acceptable salt thereof within the packaging material, and a label stating that the compound or composition, or a pharmaceutically acceptable salt thereof, tautomers, a pharmaceutically acceptable N-oxide, a pharmaceutically active a metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate is used to inhibit the activity of at least one LPA receptor, or to treat, prevent, or ameliorate one or more symptoms of a disease or condition that would benefit from inhibiting the activity of at least one receptor LPA.

VI. General synthesis, including schemes.

The compounds of the present invention can be obtained by a number of methods known to the person skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with methods of synthesis known in the field of synthetic organic chemistry, or variations thereof, as understood by a person skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reactions are carried out in a solvent or mixture of solvents suitable for the reagents and materials used and suitable for carrying out the transformations. Those skilled in the art of organic synthesis will appreciate that the functional group present on the molecule must be compatible with the proposed transformations. In some cases it will be necessary to change the order of the steps in the synthesis, or to select one and not the other scheme of a particular process, in order to obtain the target compound of the invention.

It is also recognized that another important factor in planning any synthetic route in this area is the rational choice of the protecting group used to protect the reactive functional groups present in the compounds described in the present invention. A particularly useful source describing the many alternatives for the trained professional is Greene et al., (Protective Groups in Organic Synthesis, Fourth Edition, Wiley-Interscience (2006)).

Compounds of formula (I) can be prepared using the illustrative processes described in the following Schemes and Working Examples, as well as the corresponding procedures published in the literature, which are used by a person skilled in the art. Representative reagents and procedures for these reactions are provided throughout this document and in the working examples. Protection and deprotection in the processes described below can be carried out using techniques well known in the art (see, for example, Wuts, PGM, Greene's Protective Groups in Organic Synthesis, ^5th Edition, Wiley (2014)). General methods for organic synthesis and functional group transformation can be found in Trost, BM et al., Eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, MB et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. ^7th Edition, Wiley, New York, NY (2013); Katritzky, A.R. et al., Eds., Comprehensive Organic Functional Group Transformations II, ^2nd Edition, Elsevier Science Inc.,

- 38 042829

Tarrytown, NY (2004); Larock, RC, Comprehensive Organic Transformations, ^2nd Edition, Wiley-VCH, New

York, NY (1999) and the references cited therein.

Scheme 1 describes the synthesis of N-carbamoyl-triazole-aryloxy cyclohexyl acids 16 and 17. The dihalo- (preferably dibromo-) phenyl or azine (e.g. pyridine) derivative 1 was coupled with an appropriately protected (e.g. as tetrahydropyranyl ether) propargyl alcohol 2 under Sonogashira reaction conditions (e.g., Alper, P. et al., WO 2008/097428) to give the corresponding bromo-aryl or bromo-heteroaryl protected propargyl alcohol 3. Thermal reaction of alkyne 3 with alkyl azide 4 (with or without appropriate catalyst him; Qian, Y. et al., J. Med. Chem., 2012, 55, 7920-7939 or Boren, BC, et al., J. Am. Chem. Soc., 2008, 130, 8923-8930) provides the corresponding regioisomeric protected hydroxylmethyl triazoles from which the desired regioisomer of the triazole 5 can be isolated. 1995, 60, 7508-7510) provides the corresponding pinacola boronate 6, which is then oxidized with hydrogen peroxide to give the corresponding phenol or hydroxyheteroarene 7 (Fukumoto, S. et al., WO 2012/137982). Reaction of phenol/hydroxyheteroarene 7 with 3-hydroxycycloalkyl ether 8 (e.g. cyclohexyl) under Mitsunobu reaction conditions (Kumara Swamy, KC, Chem. Rev., 2009, 109, 2551-2651) gives the corresponding triazole-cycloalkyl ether 9. Deprotection of hydroxytriazole 9 provides triazole alcohol 10, which then reacts with a brominating agent (for example, PBr ₃ or CBr ₄ /Ph ₃ P) to give triazole bromide 11. Replacing bromide 11 with NaN ₃ (or an equivalent azide reagent) gives triazolazide 12, which subjected to reduction (e.g. Staudinger reduction with Ph ₃ P/H ₂ O) to give triazolamine 13. Amine 13 is then reacted with an acylating agent 14 (e.g. chloroformate or 4-nitrophenyl carbonate) in the presence of a suitable base to give the corresponding NH-carbamate 15. Deprotection of the triazole ester group 15 provides the desired triazole carbamate cycloalkyl acids 16. Treatment of triazole NH carbamate 16 with an appropriate base (eg NaH or NaN(TMS) ₂ ) and halide R3X provides the corresponding N-alkylated carbamate cycloalkyl complex ester, which was deprotected by base-mediated hydrolysis to give triazole N-carbamoyl cycloalkyl acids 17.

Scheme 1

- 39 042829

For a specific example of analogues 20 where R ² = CH3 (Scheme 1A), instead of using an alkyl azide for cycloaddition to the protected hydroxyalkyl alkyne 3, trimethylsilyl azide is a suitable replacement reagent (Qian, Y. et al., J. Med. Chem., 2012 , 55, 7920-7939), which can be used under thermal or transition metal catalyzed conditions (Boren, BC et. al., J. Am. Chem. Soc., 2008, 130, 8923-8930). Under these conditions, the desired triazole regioisomer 18 is obtained as the main product of the 1,3-dipolar cycloaddition reaction. The trimethylsilyl group 18 is removed under standard desilylation conditions (e.g. Bu4NF, as in Qian, Y. et al., J. Med. Chem., 2012, 55, 7920-7939) to give N-methyltriazole 19 (corresponds to 5, where R ⁵ =CH ₃ ) which is then converted to N-carbamoyl-triazole of cyclohexyl acids 20 according to the synthesis sequences described in Scheme 1 (ie from 5 and 16 and 17).

Scheme 1A

R ⁵ = CH ₃ ; R ³ = H, alkyl

Scheme 2 describes an alternative route for the synthesis of N-carbamoyl triazole-aryloxy cyclohexyl acids 16 or 17. The dihalo (preferably dibromo) phenyl or azine (e.g. pyridine) derivative 1 is coupled with propargyl alcohol under Sonogashira reaction conditions (Alper, P. et al ., WO 2008/097428) to give the corresponding bromo-aryl or bromo-heteroaryl propargyl alcohol 21. Thermal reaction of alkyne 21 with alkyl azide 4 (with or without suitable catalyst, Qian, Y. et al., J. Med. Chem. , 2012, 55, 7920-7939; Boren, BC et al., J. Am. Chem. Soc., 2008, 130, 8923-8930) provides the corresponding regioisomeric hydroxymethyl triazoles from which the regioisomer of triazole 22 can be isolated. The triazole alcohol 18 is then reacted with a brominating agent (e.g. PBr ₃ or CBr ₄ /Ph ₃ P) to give the corresponding bromide 23. Replacing bromide 23 with NaN ₃ (or other suitable azide reagents) gives azide 24 which is reduced ( e.g. Staudinger reduction with Ph ₃ P/H ₂ O) to give triazolamine 25. Protection of triazolamine 25 gives intermediate 26. Bromo-aryl/heteroaryl triazole 26 is then converted to the corresponding hydroxy-aryl/heteroaryl triazole 27 via the corresponding boronate with using the same two-step sequence [borylation in the presence of a B ₂ (pin) ₂ /Pd catalyst followed by H ₂ O ₂ -mediated boronate oxidation] as described in Scheme 1. The hydroxyaryl triazole 27 is then subjected to a Mitsunobu reaction with 3-hydroxycycloalkyl ether 8 c the corresponding triazole cycloalkyl ester 28. The amine 28 is deprotected to give the basic triazolamine intermediate 13, which is then converted to the N-carbamic acids 16 or 17 using the synthesis sequences described in Scheme 1.

Scheme 2

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Scheme 3 describes an alternative route for the synthesis of triazole N-carbamate of cyclohexyl acids 16 and 17. The reaction of triazolamine 25 with an acylating reagent 14 in the presence of a base provides triazole N-carbamate 29. Bromo-aryl/heteroaryl triazole 29 is converted to the corresponding hydroxyaryl/heteroaryl triazole 30 through the corresponding boronate using the two-step sequence [B ₂ (pin) ₂ /Pd catalyst followed by H ₂ O ₂ oxidation] as described in Scheme 1. Hydroxyaryl/heteroaryl triazole 30 is reacted by Mitsunobu with 3-hydroxy cycloalkyl ether 8 to give the corresponding triazole N-carbamate cycloalkyl ester 15. This key triazole N-carbamate intermediate 15 is then converted to N-carbamate acids 16 and 17 as described in Scheme 1.

Scheme 3

when R ³ * H

Scheme 4 describes an alternative route for the synthesis of triazole N-carbamate of cyclohexyl acids 16 and 17. Reaction of an alkoxyphenyl or azine (e.g., pyridine or pyrazine) derivative 31 with trimethylsilyl acetylene under Sonogashira reaction conditions (Alper, P. et al., WO 2008/097428 ) gives the corresponding alkoxyaryl- or heteroarylsilylacetylene, which is then desilylated under standard conditions (e.g. Bu4NF) to give the alkyne 32. Thermal reaction of the alkyne 32 with sodium azide gives the corresponding triazole (Roehrig, U. et al., WO 2009/127669), which then alkylate with alkyl iodide 25 in the presence of a base to give a mixture of regioisomeric alkylated triazoles from which the desired regioisomer of triazole 33 can be isolated. e.g. dimethylformamide) provides triazolaldehyde 34. Deprotection of the alkoxy group of the arene/heteroarene 34 followed by re-protection of the phenol/hydroxy-heteroarene with a more labile protecting group (e.g. tert-butyldimethylsilyl ether) gives the protected aryl/heteroaryltriazolaldehyde 35 which is then reduced using standard methods (e.g. , NaBH4) to the corresponding triazole alcohol 36. The triazole alcohol 36 is converted to triazolamine 37 using the same 3-step sequence as described in Scheme 1 (10^13). Triazolamine 37 is then reacted with an acylating reagent 14 in the presence of a base, then deprotected to give triazole N-carbamate 30. The key hydroxyaryl/heteroaryl-triazole intermediate 30 is then converted to N-carbamic acids 16 and 17 as described in Scheme 3.

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Scheme 4

Scheme 5 describes the synthesis of N-carbamoyltriazole-aryloxy-a-fluoro-cyclohexyl acids 44 and 45. Diels-Alder reaction of 1,3-butadiene and an appropriately protected 2-fluoroacrylate ester (e.g., method of Kotikyan et al., Bull. Acad. Sci. USSR, Division of Chemical Science (Engl.), 1971, 20, 292) gives α-F cyclohexyl ester 38. Deprotection of ester 38 (eg hydrolysis) provides acid 39. Iodolactonization (eg Nols0e , JMJ et al., Eur. J. Org. Chem., 2014, 3051-3065) of an alkene with carboxylic acid 38 gives iodolactone 39. Radical-mediated deiodination (e.g. AIBN/(TMS) ₃ SiH, ref. Chatgilialoglu, C. et al., Molecules, 2012, 17, 527-555) or hydrogenolysis conditions provide the lactone 41. Acid-mediated ring opening of the lactone 41 in the presence of an alcohol provides the protected α-fluorocyclohexyl ester 42. The hydroxyester 42 is then subjected to the Mitsunobu reaction with hydroxyaryl/ hydroxy-heteroaryl-triazole 7 to give the corresponding triazole cyclohexyl ether 43 as described in Scheme 1. N-carbamoyl-methyltriazole aryloxy-a-fluoro-cyclohexyl acids 44 and 45 were synthesized from triazole a-fluoro-cyclohexyl ester 43 as follows the general synthesis procedures described in Scheme 1.

Scheme 5

Scheme 6 describes the synthesis of N-carbamoyl-methyltriazole-aryloxy-cyclohexyl acids 44 and 45. The addition of an organoalkyl metal reagent (for example, R ^7a Li or R ^7a MgX) to aldehyde 35 provides the formation of triazole alcohol 46, which is then protected as 47. Deprotection hydroxyarene/hydroxyheteroarene followed by Mitsunobu reaction with 8 provides the cyclohexyl triazole ester 48. Deprotection of 48 gives alcohol 49, which can be used to obtain cyclohexyl N-carbamate-triazole acids 50 and 51 following the general synthesis procedure described in Scheme 1.

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Scheme 6

Scheme 7 describes the synthesis of directly bonded N-carbamoyl triazole acids 54 and 55. Oxidation of triazole alcohol cyclohexyl ester 10 to carboxylic acid 52 (e.g. directly to acid with pyridinium dichromate or using a two-step procedure via an aldehyde [Swern oxidation or periodinan Dess-Martin followed by oxidation of NaClO ₂ to an acid, eg Lindgren, B. O., Acta Chem Scand 1973, 27, 888]). Curtius rearrangement 52 in the presence of the alcohol R4-OH provides the triazole NH-carbamate 53. Deprotection of the triazole NH-carbamate ester 53 provides the triazole NH-carbamate acids 54. Alternatively, the cyclohexyl ester NH-carbamate 53 is deprotonated with an appropriate base and alkylated (as in scheme 1) using alkyl K ³ -halide to obtain triazole-N-alkylcarbamate acids 55.

Scheme 7

Scheme 8 describes the synthesis of N-carbamoyl triazole-aryloxy-cyclohexyl acids 59 and 60. The triazole alcohol 10 is oxidized to the corresponding aldehyde (e.g. Dess-Martin periodinane or Swern oxidation), which is then subjected to an olefination reaction (e.g. Wittig olefinization or Peterson), which provides terminal olefin 56. Hydroboration of olefin 56 at the terminal carbon (for example, with 9-BBN) followed by oxidative treatment provides the corresponding triazole-ethyl alcohol 57. Triazole-ethyl alcohol 57 is subjected to a 3-step sequence described in the scheme 1 (bromination, azide exchange, azide reduction) to give the key triazole-ethylamine intermediate 58. Triazolethylamine 58 is then used to prepare the triazol-ethyl-N-carbamate of cyclohexyl acids 59 and 60 using the same synthesis sequence as described for the conversion of the amine 13 to triazole-carbamate acids 16 and 17 in Scheme 1.

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Scheme 8

⁵⁶ 57

when R ³ * H

Scheme 9 describes the synthesis of N-ureido-triazole-aryloxycyclohexyl acids 63 and 65. The triazolamine-cyclohexyl ester 13 reacts with carbamoyl chloride 62 (obtained, for example, from the reaction of secondary amine 61 with triphosgene) to give the corresponding ureido-triazole cyclohexyl ester ester, which is then deprotected to give N,N'-dialkyl-ureido-triazole-aryloxycyclohexyl acids 63. In an additional synthetic route, triazolamine-cyclohexyl ester 13 is reacted directly with triphosgene to give carbamoyl chloride 64 (CDI to give the corresponding intermediate compounds), which reacts with the primary amine R ³ -NH ₂ (or secondary amine 61) to give (after deprotection from the ester) the corresponding N-alkyl-ureido-triazole-aryloxycyclohexyl acids 65 (with secondary amines, the products are N ,N'-dialkylureidotriazole acids 63).

Scheme 9

Tryphosgene 9

HN-R ³ ---------► _S |-L ₃

R ⁴ Base, ^ ^-R . . p4 (nair., pyridine)

64 65

Scheme 10 describes the synthesis of triazole-N-linked urea-cyclohexyl acids 67 and 68. Triazole-alcohol cyclohexyl ester 10 is oxidized to triazole-carboxylic acid 66 (for example, directly to the acid using, for example, pyridinium dichromate or using 2 -step procedure via aldehyde [Svern oxidation or Dess-Martin periodinane followed by oxidation of NaClO ₂ to an acid, eg Lindgren, B.O., Acta Chem. Scand. 1973, 27, 888]). Curtsis rearrangement (for example, with (PhO) ₂ PON ₃ ) triazolic acid 66 provides the corresponding triazole-isocyanate intermediate, which then reacts with either the primary amine R ³ NH ₂ or the secondary amine R ³ R ⁴ NH to form, after deprotection, the complex ester of triazole-ureido-NH-alkyl-cyclohexyl acids 67 or triazole-ureido-N,N-dialkylcyclohexyl acids 68.

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Scheme 10

Curtsis rearrangement, eg, (PhO) ₂ PON ₃

2) R ³ NH ₂

3) Acid deprotection

Curtsis rearrangement, eg, (PhO) ₂ PON ₃

2) R ³ R ⁴ NH

3) Acid deprotection

Scheme 11 describes the synthesis of triazolesulfonylureidocyclohexyl acids 70. Triazoleaminecyclohexyl ether 13 reacts with dialkylsulfamoyl chloride 69 (obtained from the reaction of secondary amine 61 with sulphurous chloride) to give the corresponding sulfonylureidotriazolecyclohexyl ether, which is then deprotected to give sulfonylureido-triazole-aryloxy-cyclohexyl acids 70.

Scheme 11

VII. Examples.

The following examples are offered by way of illustration, partial scope, and specific embodiments of the invention and are not intended to limit the scope of the invention. Abbreviations and chemical symbols have their usual and customary meanings unless otherwise noted. Unless otherwise indicated, the compounds described herein have been prepared, isolated, and characterized using the schemes and other methods disclosed herein, or may be prepared using them.

If necessary, the reactions were carried out in an atmosphere of dry nitrogen (or argon). For anhydrous reactions, DRISOLV® solvents from EM were used. For other reactions, assay grade or HPLC grade solvents were used. Unless otherwise noted, all commercially obtained reagents were used as received.

Microwave activation reactions were performed in a 400 W Biotage Initiator microwave reactor in microwave reaction vessels with microwave (2.5 GHz) radiation.

HPLC/MS and preparative/analytical HPLC methods were used to characterize or purify compounds by example.

NMR (Nuclear Magnetic Resonance) spectra were usually obtained on Bruker or JEOL 400 and 500 MHz instruments in the indicated solvents. All chemical shifts are given in parts per million (ppm) relative to tetramethylsilane with the solvent resonance signal as an internal standard. 1H NMR data are usually presented as follows: chemical shift, multiplicity (s = singlet, br s = wide singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, sep = septet, m = multiplet, app = apparent), coupling constants (Hz) and integration.

In examples where 1H NMR spectra were collected in d ₆ -DMSO, a water suppression sequence was often used. This sequence effectively suppresses the water signal and any proton peaks in the same region, typically between 3.30-3.65 ppm, which affects the overall proton integration.

The term HPLC refers to a Shimadzu high performance liquid chromatography chromatograph using one of the following methods:

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HPLC-1: Sunfire C18 (4.6x150 mm) 3.5 µm column, gradient 10 to 100% B: A for 12 min, then hold for 3 min at 100% B; mobile phase A: 0.05% TFA in water: CH ₃ CN (95:5);

mobile phase B: 0.05% TFA in CH ₃ CN:water (95:5); TFA buffer, pH 2.5; flow rate: 1 ml/min; wavelength: 254, 220 nm;

HPLC-2: XBridge Phenyl (4.6x150 mm) 3.5 µm gradient 10 to 100% B: A for 12 min, then hold for 3 min at 100% B; mobile phase A: 0.05% TFA in water: CH ₃ CN (95:5); mobile phase B: 0.05% TFA in CH ₃ CN:water (95:5); TFA buffer, pH 2.5; flow rate: 1 ml/min; wavelength: 254, 220 nm.

HPLC-3: Chiralpak AD-H, 4.6x250 mm, 5 µm; mobile phase: 30% EtOH-heptane (1:1)/70% CO2; flow rate: 40 ml/min, 100 bar, 35°C; wavelength: 220 nm.

HPLC-4: Waters Acquity UPLC WEN C18, 2.1x50 mm, particles 1.7 µm; mobile phase A: 5:95 CH ₃ CN: water with 10 mM NH ₄ OAc; mobile phase B: 95:5 CH ₃ CN: water with 10 mM NH ₄ OAc; temperature: 50°C; gradient: 0-100% B over 3 min, then hold for 0.75 min at 100% B; flow rate: 1.11 ml/min; detection: UV at 220 nm.

HPLC-5: Waters Acquity UPLC WEN C18, 2.1x50 mm, particles 1.7 µm; mobile phase A: 5:95 CH ₃ CN: water with 0.1% TFA; mobile phase B: 95:5 CH ₃ CN: water with 0.1% TFA; temperature: 50°C; gradient: 0-100% B over 3 min, then hold for 0.75 min at 100% B; flow rate: 1.11 ml/min; detection: UV at 220 nm.

Intermediate 1. (±)-cis-Isopropyl 1-fluoro-3-hydroxycyclohexanecarboxylate

Intermediate 1A. (±)-Ethyl 1-fluorocyclohex-3-ene carboxylate

A mixture of 20% buta-1,3-diene in toluene (13.8 ml, 41.1 mmol) and ethyl 2-fluoroacrylate (3.07 ml, 27.4 mmol) was heated at 120° C. in a sealed tube for 7 days, then cooled to room temperature and concentrated in vacuo. The residue was chromatographed (80 g SiO ₂ ; continuous gradient from 0 to 10% EtOAc in hexane over 20 min) to give Intermediate 1A (3.80 g, 22.1 mmol, 80% yield) as a clear oil.

1H NMR (500 MHz, CDC13) δ 5.79 (ddd, J=9.9, 4.7, 2.2 Hz, 1H), 5.64-5.58 (m, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.73-2.57 ( m, 1H), 2.45-2.23 (m, 2H), 2.20-1.91 (m, 3H), 1.32 (t, J=7.2 Hz, 3H);

¹⁹ F NMR (471 MHz, CDC13) δ -162.69 (s, 1F).

Intermediate 1B. (±)-1-Fluorocyclohex-3-ene carboxylic acid

A mixture of intermediate 1A (3.80 g, 22.1 mmol) and aq. LiOH (55.2 ml of a 2.0 M solution, 110 mmol) in THF (50 ml) was stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 2 with conc. HCl (9.19 ml, 110 mmol) and then extracted with EtOAc (3x25 ml). The combined organic extracts were washed with water and concentrated in vacuo to give Intermediate 1B (3.0 g, 20.8 mmol, 94% yield) as a light yellowish oil.

1H NMR (500 MHz, CDCI3) δ 5.81 (ddd, J=9.8, 4.6, 2.1 Hz, 1H), 5.66-5.58 (m, 1H), 2.76-2.59 (m, 1H), 2.49-2.37 (m, 1H ), 2.35-2.23 (m, 1H), 2.22-1.92 (m, 3H);

¹⁹ F NMR (471 MHz, CDCl·,) δ -163.02 (s, 1F).

Intermediate 1C. (±)-1-Fluoro-4-iodine-6-oxabicyclo[3.2.1]octan-7-one

To a mixture of intermediate 1B (3.0 g, 20.8 mmol) in water (20 ml) was added NaHCO ₃ (5.25 g, 62.4 mmol) in portions and the mixture was stirred until it became homogeneous. An aqueous solution of I ₂ (obtained by dissolving I ₂ (5.81 g, 22.0 mmol) and KI (20.7 g, 125 mmol) in 20 ml of water) was added and the reaction mixture was stirred overnight at room temperature in the dark . Then water (100 ml) was added and the mixture was extracted with DCM (3x25 ml), washed with 10% aq. Na ₂ S ₂ O ₃ (2x20 ml) and water, dried (MgSO ₄ ) and concentrated in vacuo. The residual crude oil was chromatographed (80 g SiO ₂ ; continuous gradient from 0 to 50% EtOAc in hexane over 20 min) to give Intermediate 1C (3.53 g, 13.1 mmol, 62.8% yield) as white solid.

1H NMR (500 MHz, CDCl ₃ ) δ 4.89 (dt, J=6.5, 3.5 Hz, 1H), 4.44 (q, J=4.6 Hz, 1H), 3.08 (dd, J=11.6, 1.9 Hz,

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1H), 2.75 (tddd, J=11.3, 6.5, 3.3, 1.1 Hz, 1H), 2.50-2.38 (m, 1H), 2.34-2.17 (m, 2H), 2.11-1.99 (m, 1H);

¹³ C NMR (126 MHz, CDCI3) δ 172.2, 172.0, 93.6, 91.9, 78.4, 78.3, 39.2, 39.0, 29.7, 29.6, 28.4, 28.2, 20.2;

¹⁹ F NMR (471 MHz, CDCl ₃ ) δ -167.97 (s, 1F).

Intermediate connection 1D. (±)-1-Fluoro-6-oxabicyclo[3.2.1]octan-7-one

To a solution of intermediate 1C (350 mg, 1.30 mmol) and AIBN (21 mg, 0.130 mmol) in benzene (5 mL) was added tris-(trimethylsilyl)silane (0.60 mL, 1.94 mmol) in portions over 10 min at 60°C. The reaction mixture was stirred at 70°C for 2 h, cooled to room temperature and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NH ₄ Cl, dried (MgSO ₄ ) and concentrated in vacuo. The crude oil was chromatographed (12 g SiO ₂ ; continuous gradient from 0 to 30% EtOAc in hexane over 10 min) to give Intermediate 1D (124 mg, 0.860 mmol, 66.4% yield) as a white solid.

¹⁹ F NMR (471 MHz, CDCl ₃ ) δ -167.01 (s, 1F);

¹ H NMR (500 MHz, CDCl3) δ 4.98-4.81 (m, 1H), 2.75 (dtdd, J=15.9, 6.8, 3.3, 1.7 Hz, 1H), 2.24-1.89 (m, 5H), 1.82-1.65 ( m, 1H), 1.60-1.46 (m, 1H);

^13C NMR (126 MHz, _CDCl3 ) δ 173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9, 31.3, 31.1, 26.7, 17.7, 17.6.

Intermediate 1.

Acetyl chloride (0.061 ml, 0.860 mmol) was added portionwise to isopropanol (3 ml) at 0° C. and then stirred at room temperature for 30 minutes. Intermediate 1D (124 mg, 0.860 mmol) was added and the reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The residual crude oil was chromatographed (4 g SiO2; continuous gradient from 0 to 50% EtOAc in hexane over 10 min) to give Intermediate 1 (140 mg, 0.685 mmol, 80% yield) as a clear oil.

1H NMR (500 MHz, CDCl3) δ 5.08 (spt, J=6.3 Hz, 1H), 3.91 (tt, J=10.9, 4.4 Hz, 1H), 2.68 (br. s., 1H), 2.28 (dddt, J =13.5, 9.0, 4.6, 2.1 Hz, 1H), 2.06-1.98 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.62 (m, 4H), 1.37-1.22 (m, 7H);

¹⁹ F NMR (471 MHz, CDCl3) δ -162.93 (s, 1F); ¹³ C NMR (126 MHz, CDCl3) δ 170.9, 170.7, 95.7, 94.2, 69.3, 66.1, 40.7, 40.5, 33.9, 31.6, 31.4, 21.5, 19.1.

Example 1

(1S,3 S)-3 -((2-Methyl-6-(1-methyl-5 -(((((S)-2-methylbutoxy)carbonyl)amino)methyl)- 1H-1,2,3 -triazol4-yl)pyridin-3 -yl)oxy)cyclohexanecarboxylic acid

Ag™ A :

Ν-Ν _χ ^Μ =

1A. 3-Bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine ^vg ^GA = \2=N OTNR

To a solution of 2,5-dibromo-6-methylpyridine (5 g, 21.11 mmol) and 2-(prop-2-yn-1-yloxy)tetrahydro-2Hpyran (4.44 g, 31.7 mmol) in MeCN (42.2 ml) was added Et ₃ N (8.83 ml, 63.3 mmol). The solution was degassed under N2, then (Ph ₃ ) ₂ PdCl ₂ (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06 mmol) were added. The reaction mixture was stirred at room temperature for 14 h, after which the reaction mixture was filtered through a pad of Celite® and the pad was washed with EtOAc (2x10 mL). The combined filtrates were concentrated in vacuo and the residue was chromatographed (SiO2; continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, yield 96%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.3, 2.3 Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t, J=3.3 Hz, 1H), 4.61-4.45 (m, 2H), 3.98-3.81 (m, 1H), 3.66-3.44 (m, 1H), 1.92-1.73 (m, 2H), 1.721. 52(m, 2H).

LCMS [M+H]+ = 298.0.

1B. 3-Bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4yl)pyridine

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A solution of the compound of example 1A (6.0 g, 20.3 mmol) in toluene (20 ml) and TMSCH ₂ N ₃ (7.85 g, 60.8 mmol) was heated at 90° C. under Ar for 15 h , then cooled to room temperature. The volatiles were removed in vacuo and the residue was dissolved in THF (20 ml). TBAF (20.3 ml of a 1 M solution in THF, 20.3 mmol) was added to the mixture at 0°C. After stirring for 10 minutes, the reaction was complete as determined by analytical HPLC. Volatiles were removed in vacuo and the residue was subjected to chromatography (SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound (2.1 g, 29% yield) as a white solid.

1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.03 (br. s., 1H), 5.39-5.23 (m, 4H ), 4.81-4.76 (m, 1H), 4.17 (s, 3H), 3.91 (ddd, J=11.3, 7.9, 3.3 Hz, 1H), 3.65-3.48 (m, 1H), 2.54 (s, 3H), 1.88-1.68 (m, 2H), 1.56 (br. s., 2H).

1C. 2-Methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4yl)pyridin-3-ol

N /Ayanr

N-N \

To a degassed solution (sparged 3 times with Ar) of Example 1B (213 mg, 0.60 mmol), bis(pinacolato)diborone (230 mg, 0.91 mmol) and KOAc (178 mg, 1.81 mmol) in THF was added Pd(dppf)Cl ₂ (22 mg, 0.03 mmol). The reaction mixture was heated in a sealed tube at 80°C for 16 h, then cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3x20 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude boronate product was used in the next step without further purification. To a solution of the crude product, 2-(1-methyl-5(((tetrahydro-2H-pyran-2-yl)oxy)-methyl)-1H-1,2,3-triazol-4-yl)-5-( H ₂ O ₂ (0.19 ml 30% aqueous solution, 6.0 mmol). The reaction mixture was stirred at room temperature for 1 h, then cooled to 0°C and quenched by slowly adding saturated aqueous Na ₂ S ₂ O ₃ . The aqueous layer was extracted with EtOAc (3x20 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was subjected to chromatography (ISCO SiO ₂ column, continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound (150 mg, 86%) as a white solid.

1H NMR (400M Hz, CDCl3) δ 8.27 (d, J=2.6 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.29-7.21 (m, 1H), 5.33 (s, 1H), 5.28 (d, J=2.4 Hz, 2H), 4.76 (s, 1H), 4.18 (s, 3H), 3.90 (s, 1H), 3.63-3.48 (m, 1H), 1.72 (s, 2H), 1.65- 1.51(m, 2H).

LCMS [M+H]+ = 291.2.

1D. Isopropyl (1 S, 3S) -3 - ((2-methyl-6- ( 1 -methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) - 1H-1,2,3 triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of the compound of example 1C (1.18 g, 4.06 mmol) and (1S,3R)-isopropyl-3hydroxycyclohexanecarboxylate (synthesized according to the method described in US2007/0197788A1, 1.51 g, 8.13 mmol) in toluene (81 ml) added Bu ₃ P (3.17 ml, 12.2 mmol). To this stirred mixture was added (E)-diazen-1,2-diyl-bis-(piperidin-1-yl-methanone) (3.08 g, 12.2 mmol) in portions and the reaction mixture was heated at 50° C. for 120 min, then cooled to room temperature. At this point, the LC-MS spectrum of the reaction mixture showed the presence of the desired product. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed (SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound (1.2 g, 2.62 mmol, 64.4% yield) as a white foam.

1Н NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 5.45-5.24 (m, 2H), 5.04 (dt, J=12.5 , 6.3 Hz, 1H), 4.83-4.64 (m, 2Н), 4.16 (s, 3Н), 3.91 (ddd, J=11.2, 7.9, 3.1 Hz, 1H), 3.64-3.48 (m, 1H), 2.93- 2.71 (m, 1H), 2.52 (s, 3H), 2.23-1.45 (m, 14H), 1.26 (dd, J=6.4, 2.0 Hz, 6H).

1E. Isopropyl (1 S,3S)-3 -((6-(5-(hydroxymethyl)-1 -methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy)cyclohexane -1-carboxylate

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To a solution of the compound from example 1D (1.7 g, 3.71 mmol) in MeOH (37 ml) was added PPTS (0.932 g, 3.71 mmol). The reaction mixture was heated to 60°C for 2 h, then cooled to room temperature, diluted with water and saturated aqueous NaHCO ₃ then was extracted with EtOAc (3x10 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), concentrated in vacuo and chromatographed (SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound as a white foam (1.36 g, 3.63 mmol, 98% yield.

¹ H NMR (400 MHz, CDCl3) 5 8.01 (d, J=8.6 Hz, 1H), 7.46 (d, J=5.1 Hz, 1H), 7.27-7.15 (m, 1H), 4.96 (dt, J=12.5 , 6.3 Hz, 1H), 4.74 (s, 2H), 4.66-4.59 (m, 1H), 4.00 (s, 3H), 2.80-2.64 (m, 1H), 2.46 (s, 3H), 2.07-1.50 ( m, 8H), 1.18 (dd, J=6.4, 2.2 Hz, 6H).

1F. (1 S,3 S)-isopropyl 3 -((6-(5-(bromomethyl)-1 -methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy) cyclohexanecarboxylate

To a solution of the compound from example 1E (0.28 g, 0.721 mmol) in DME (7 ml) was added PBr ₃ (0.17 ml, 1.80 mmol) at 0°C. The reaction mixture was stirred overnight at room temperature, then cooled to 0°C and neutralized with saturated aqueous NaHCO ₃ to pH ~7. The mixture was partitioned between EtOAc (50 ml) and water (5 ml) and the aqueous layer was extracted with EtOAc (3x10 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed (12 g SiO ₂ ; continuous gradient 0 to 50% EtOAc/hexanes over 25 min) to give the title compound (300 mg, 0.665 mmol, 92% yield) as a white solid.

LCMS [M+H]+ = 451.2.

1H NMR (500 MHz, CDCl ₃ ) δ 7.99 (d, J=8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 5.26 (d, J=1.4 Hz, 2H), 5.03 (spt, J=6.3 Hz, 1H), 4.75-4.63 (m, 1H), 4.12 (s, 3H), 2.82-2.74 (m, 1H), 2.54 (s, 3H), 2.14-2.07 (m, 1H), 1.991 .88 (m, 3H), 1.81-1.59 (m, 4H), 1.27-1.24 (m, 6H).

1g. (1 S,3 S)-Isopropyl 3 -((6-(5-(azidomethyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy) cyclohexanecarboxylate

To a solution of the compound from example 1F (100 mg, 0.222 mmol) in DMF (1.5 ml) was added NaN ₃ (36 mg, 0.554 mmol) and the reaction mixture was stirred at 80°C for 1 h, then cooled to room temperature. LCMS analysis showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water and the mixture was stirred at room temperature for 15 minutes. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude title compound, which was used in the next step without further purification.

LCMS [M+H] ⁺ = 414.3.

1H. (1 S,3S)-Isopropyl 3-((6-(5-(aminomethyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy)cyclohexanecarboxylate

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To a solution of the compound from example 1G (92 mg, 0.22 mmol) in THF (1 ml) and H ₂ O (0.3 ml) was added Ph ₃ P (58 mg, 0.22 mmol) and the reaction mixture was stirred at room temperature. temperature during the night. The reaction mixture was partitioned between EtOAc and water and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was subjected to chromatography (12 g SiO ₂ ; 100% EtOAc for 10 min and then a gradient of 0 to 10% MeOH in CH ₂ Cl ₂ over 20 min; flow rate: 30 ml/min) to obtain the title compound ( 81 mg, 0.21 mmol, 94% yield as a beige oil.

LCMS [M+H] ⁺ = 388.3.

Example 1

To a solution of the compound from example 1H (8 mg, 0.021 mmol) and (S)-2-methylbutyl (4-nitrophenyl) carbonate (7 mg, 0.027 mmol) in THF (0.4 ml) was added N-ethyl-N-isopropylpropane -2-amine (11 µl, 0.062 mmol). The mixture was stirred at room temperature for 1 h, after which THF (0.8 ml)/H ₂ O (0.4 ml)/MeOH (0.4 ml) and LiOH H ₂ O (5 mg, 0.105 mmol) were added ). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and diluted with H ₂ O (5 ml). The pH value of the mixture was adjusted with 1y/ aq. HCl to ~5 and extracted with EtOAc (3x5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residual crude product was purified by preparative LC/MS. Column: Waters XBridge C18, 19x200 mm, particles 5 µm; Guard column: Waters Xbridge C18, 19x10 mm, 5 µm particles; mobile phase A: 5:95 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 95:5 MeCN:H ₂ O with 0.1% TFA; gradient: 50-90% B over 20 min, then hold for 5 min at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were concentrated in vacuo by centrifugal evaporation to give the title compound (6.6 mg, 0.014 mmol, 68% yield).

LCMS [M+H]+ = 460.3.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.80 (d, J=8.2 Hz, 1H), 7.55 (br.s., 1H), 7.46 (d, J=8.7 Hz, 1H), 4.80 4.62 ( m, 3Н), 4.02 (s, 3Н), 3.76-3.67 (m, 2H), 2.62-2.55 (m, 1H), 2.42 (s, 3Н), 2.04-0.93 (m, 11Н), 0.83-0.72 ( m, 6H).

hLPA1 IC50 = 18 nM.

Example 2

(1S,3S)-3-((2-Methyl-6-(1-methyl-5-((methyl(((S)-2-methylbutoxy)carbonyl)amino)methyl)-1H-1,2,3triazole -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid

To a mixture of the compound of example 1 (1.7 mg, 3.70 µmol) in DMF (0.2 ml) at 0° C. under N2 was added NaH (0.5 mg of a 60% dispersion in mineral oil; 0.011 mmol) and the reaction mixture was stirred for 30 min at 0°C. Then MeI (0.7 μl, 0.011 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was dissolved in THF (0.8 ml)/MeOH (0.4 ml)/water (0.4 ml) and LiOH-H ₂ O (1 mg, 18.5 mol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and diluted with H ₂ O (5 ml). The pH value of the mixture was adjusted with 1N. aq. HCl to ~5 and the mixture was extracted with EtOAc (3x5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO ₄ ) and concentrated in vacuo. This crude product was purified by preparative LC/MS: column: Waters Xbridge C18, 19x200 mm, 5 µm particles; Guard column: Waters Xbridge C18, 19x10 mm, 5 µm particles; mobile phase A: 5:95 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 95:5 MeCN:H ₂ O with 0.1% TFA; gradient: 50-90% B over 20 min, then hold for 5 min at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were concentrated in vacuo by centrifugal evaporation to give the title compound (1 mg, 2.1 µmol, 56.5% yield).

LCMS [M+H]+ = 474.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 7.82 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.09 (br. s., 2H), 4.784.68 ( m, 1H), 4.04-3.76 (m, 5H), 2.73 (s, 3H), 2.65-2.56 (m, 1H), 2.40 (s, 3H), 1.98-1.02 (m, 11H), 0.82 (br. s., 6H). hLPA1 IC ₅₀ = 29 nM.

Example 3

(1S,3S)-3-((6-(5-(((Butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin3-yl) hydroxy)cyclohexane-1-carboxylic acid

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3A. Isopropyl (1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 1H (10 mg, 0.026 mmol) in EtOAc (0.3 mL) and saturated aqueous NaHCO ₃ (0.3 mL) was added n-butyl chloroformate (0.017 mL, 0.129 mmol) at room temperature. The reaction mixture was stirred overnight then concentrated in vacuo. This crude product was used in the next step without further purification.

LCMS [M+H] ⁺ = 488.3.

Example 3

To a solution of the crude compound from example 3A (12.7 mg, 0.026 mmol) in THF (0.8 ml)/H ₂ O (0.400 ml)/MeOH (0.400 ml) was added LiOH-H ₂ O (6 mg, 0 .13 mmol) at room temperature. The mixture was stirred at room temperature overnight, then concentrated in vacuo; the residue was diluted with H ₂ O (5 ml) and the pH was adjusted with 1N. aq. HCl up to ~5. The mixture was extracted with EtOAc (3x5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by preparative HPLC (Phenomenex Luna Axia, 5 µm, C18, 30x100 mm; 10 min gradient from 85% A:15% B to 0% A:100% B (A = 90% H2O/10%

ACN + 0.1% TFA); (B = 90% ACN/10% H ₂ O + 0.1% TFA); detection at 220 nm) to give the title compound (11.3 mg, 0.025 mmol, 98% yield).

1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=8.8 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 4.90-4.81 (m, 1H), 4.59 (s, 2H), 4.20 (s, 3Н), 4.08 (t, J=6.6 Hz, 2Н), 2.95-2.83 (m, 1H), 2.75 (s, 3Н), 2.23-2.13 (m, 1H), 2.03-1.76 (m, 6H ), 1.73-1.55 (m, 3H), 1.42-1.31 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).

LCMS [M+H] ⁺ = 446.3.

hLPA1 IC50 = 14 nM.

Example 4

(±)-(Trans)-3 -(4-(5 -((((isopentyloxy)carbonyl)amino)methyl)-1 -methyl-1H-1,2,3-triazol-4yl)phenoxy)cyclohexane-1 -carboxylic acid

4A. 2-((3-(4-Bromophenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran

To a solution of 1-bromo-4-iodobenzene (10.0 g, 35.3 mmol) in DMF (50 ml) was added TEA (25 ml, 177 mmol), CuI (0.40 g, 2.12 mmol), Pd (Ph ₃ P) ₄ (0.82 g, 0.71 mmol) and 2-(prop-2-yn-1-yloxy)tetrahydro2H-pyran (6.44 g, 46.0 mmol). The reaction mixture was stirred at room temperature under N ₂ for 16 h, then concentrated in vacuo. The residue was chromatographed (120 g SiO ₂ ; isocratic elution: hexanes/EtOAc = 95:5) to give the title compound (10.0 g, 33.9 mmol, 96% yield) as a colorless oil.

LCMS [M+Na] ⁺ = 319.0.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.46-7.42 (m, 2H), 7.33-7.29 (m, 2H), 4.89 (t, 7=3.4 Hz, 1H), 4.54-4.40 (m,

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2H), 3.89 (ddd, J=11.5, 9.0, 2.9 Hz, 1H), 3.61-3.54 (m, 1H), 1.92-1.51 (m, 6H).

4B. 4-(4-Bromophenyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H1,2,3-triazole

-sir

To a solution of 4A (3.0 g, 10.2 mmol) in toluene (10 mL) was added TMSCH2N3 (1.8 mL, 12.2 mmol). The mixture was refluxed under Ar for 15 h, then cooled to room temperature and concentrated in vacuo. The crude residue was subjected to chromatography (120 g SiO ₂ ; continuous gradient from 0 to 20% EtOAc in hexane over 25 min, then hold at 20% EtOAc for 20 min) to give the title compound (667 mg, 1.57 mmol , 15% yield) as a beige solid.

LCMS [M+H] ⁺ = 424.1.

'and NMR (500 MHz, CDCI3) δ 7.73-7.69 (m, 2H), 7.60-7.56 (m, 2H), 4.84 (d, 7=12.9 Hz, 1H), 4.70-4.64 (m, 2H), 3.87 -3.79 (m, 3H), 3.58-3.49 (m, 1H), 1.88-1.51 (m, 6H), 0.23 (s, 9H).

4C. 4-(4-Bromophenyl)-1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole

To a solution of the compound from example 4B (660 mg, 1.56 mmol) in THF (10 ml) was added H2O (0.06 ml, 3.1 mmol) and the reaction mixture was cooled to 0°C. TBAF (1.87 ml of a 1.0 M solution in THF; 1.87 mmol) was added and the reaction mixture was stirred at 0° C. for 10 minutes. Volatiles were removed in vacuo and the crude product was subjected to chromatography (40 g SiO ₂ ; continuous gradient from 100% hexane to 50:50 hexane:EtOAc for 30 min, hold at 50% hexane:EtOAc for 10 min) to obtain specified in title compound (510 mg, 1.49 mmol, 93% yield) as a beige oil.

LCMS [M+H] ⁺ = 352.0.

'H NMR (500 MHz, CDCI3) δ 7.70-7.66 (m, 2H), 7.61-7.57 (m, 2H), 4.87 (d, J=12.9 Hz, 1H), 4.74-4.65 (m, 2H), 4.15 (s, 3H), 3.82 (ddd, J=11.3, 8.1, 3.2 Hz, 1H), 3.58-3.49 (m, 1H), 1.88-1.50 (m, 6H).

4D. 4-(1-Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenol

A mixture of Pd ₂ (dba) ₃ (44 mg, 0.048 mmol), di-tert-butyl (2',4',6'-triisopropyl-[1,1'-biphenyl]-2yl)phosphine (81 mg, 0.191 mmol ), KOH (268 mg, 4.77 mmol) and Example 4C (281 mg, 0.80 mmol) in 1,4-dioxane (3 ml) and water (3 ml) were rapidly evacuated under vacuum and refilled with Ar (repeated 3 times). The mixture was stirred at 85°C for 16 h, then cooled to room temperature and carefully acidified with dilute aq. 1n. HCl. The mixture was extracted with EtOAc (4x5 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the crude product as a brown solid. This material was chromatographed (SiO ₂ ; EtOAc/hexanes) to give the title compound (210 mg, 0.726 mmol, 91% yield) as a white solid.

LCMS [M+H] ⁺ = 290.1.

4E. (±)-Trans-1,3-isopropyl 3-(4-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- 1H-1,2,3triazol-4 -yl)phenoxy)cyclohexanecarboxylate (diastereomeric mixture at tetrahydropyranyl ether)

To a mixture of the compound of Example 4D (0.19 g, 0.64 mmol), (±)-isopropyl cis-3-hydroxycyclohexane 1-carboxylate (0.21 g, 1.15 mmol), Et ₃ N (0.16 ml, 1.15 mmol) and Ph ₃ P (0.30 g, 1.15 mmol) in THF (4 ml) and

- 52 042829 was added dropwise DIAD (0.22 ml, 1.15 mmol). The reaction mixture was stirred overnight at room temperature. Was added water (4 ml) and the reaction mixture was acidified with 1N. aq. HCl and extracted with EtOAc (3x10 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was chromatographed (40 g SiO ₂ ; continuous gradient from 0 to 80% EtOAc in hexanes over 30 min and at 80% EtOAc/hexanes over 20 min) to give the title compound (0.12 g, 0.257 mmol , 40% yield) as a beige oil.

LCMS [M+H]+ = 458.1.

4F. (±)-Trans-1,3-isopropyl 3-(4-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a solution of the compound from example 4E (115 mg, 0.251 mmol) in MeOH (2.5 ml) was added PPTS (6 mg, 0.025 mmol). The reaction mixture was stirred overnight at room temperature. LCMS showed that the reaction was still not complete, so the mixture was heated at 60°C for another 6 h, then cooled to room temperature. The mixture was concentrated in vacuo and the residue was chromatographed (12 g SiO ₂ ; continuous gradient 80-100% EtOAc in hexanes over 10 min) to give the title compound (84 mg, 90% yield) as a brown oil.

LCMS [M+H] ⁺ = 374.2.

4G. (±)-Trans-1,3-isopropyl 3-(4-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a mixture of the compound from example 4F (84 mg, 0.225 mmol) and CBr ₄ (82 mg, 0.247 mmol) in DCM (1.2 ml) was added Ph ₃ P (65 mg, 0.247 mmol) in portions. The reaction mixture was allowed to slowly warm to room temperature overnight, then concentrated in vacuo. The residue was subjected to chromatography (12 g SiO ₂ ; continuous gradient 25 min from 0 to 70% EtOAc in hexane; flow rate = 30 ml/min). Pure fractions were concentrated in vacuo to give the title compound (66 mg, 0.151 mmol, 67% yield) as a colorless oil.

LCMS [M+H] ⁺ = 436.0.

4H. (±)-Trans-1,3-isopropyl 3-(4-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a solution of the compound from example 4G (65 mg, 0.149 mmol) in DMF (1 ml) was added NaN ₃ (24 mg, 0.37 mmol) and the reaction mixture was stirred at 80°C for 1 h, then cooled to room temperature. LCMS analysis showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water (5 ml each) and the resulting mixture was stirred at room temperature. After 15 min the organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude azide product was used in the next step without further purification.

4I. (±)-Trans-1,3-isopropyl 3-(4-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

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Ph ₃ P (39 mg, 0.149 mmol) was added to a solution of the compound from example 4H (59 mg, 0.149 mmol) in THF (0.6 ml) and H2O (0.2 ml) and the reaction mixture was stirred at room temperature overnight . The reaction mixture was partitioned between EtOAc and water (5 ml each) and the resulting mixture was stirred at room temperature. After 15 min the organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was subjected to chromatography (8 g SiO ₂ ; 100% EtOAc for 10 min, then a continuous gradient from 0 to 10% MeOH in CH ₂ Cl ₂ over 15 min; flow rate: 30 ml/min) to give the title compound (47 mg, 0.126 mmol, 84% yield) as a beige oil.

LCMS [M+H]+ = 373.1.

Example 4

A solution of 3-methylbutan-1-ol (6 mg, 0.064 mmol), CDI (11 mg, 0.064 mmol) and LiOH-H ₂ O (3 mg, 0.11 mmol) in toluene (0.5 ml) was stirred at 60 °C for 2 hours. To this mixture was added the compound of example 4I (8 mg, 0.021 mmol) and the reaction mixture was stirred at 60°C overnight, then cooled to room temperature. The mixture was partitioned between EtOAc and water; the aqueous phase was extracted with EtOAc (3 times) and the combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. To a solution of this crude product in THF (0.8 ml) and H ₂ O (0.40 ml) and MeOH (0.40 ml) was added LiOH-H ₂ O (7 mg, 0.168 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and diluted with water (5 ml). The pH of the mixture was adjusted with aq. 1n. HCl to pH ~3 and was extracted with EtOAc (3x5 ml). The combined organic extracts were washed with brine (2 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by preparative LC/MS: column: Waters XBridge C18, 19x200 mm, 5 µm particles; Guard column: Waters XBridge C18, 19x10 mm, 5 µm particles; mobile phase A: 5:95 MeCN^O with 0.1% TFA; mobile phase B: 95:5 MeCN^O with 0.1% TFA; gradient: 50-90% B over 20 min, then hold for 5 min at 100% B; flow rate: 20 ml/min) to give the title compound (1.4 mg, 3.15 μmol, 15% yield). LCMS [M+H] ⁺ = 445.1.

1H NMR (500 MHz, DMSO-d ₆ ) δ 7.77 (br. s., 1H), 7.63 (d, J=7.6 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 4.724.64 ( m, 1H), 4.41 (d, J=5.2 Hz, 2H), 4.06-3.94 (m, 5H), 2.70-2.59 (m, 1H), 1.98-1.34 (m, 11H), 0.86 (d, J= 6.1 Hz, 6H).

hLPA1 IC50 = 148 nM.

Example 5

(1S,3 S)-3-((6-(5-(((Butoxycarbonyl)amino)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3yl)oxy )cyclohexane-1-carboxylic acid /OH

N-N^ Η O

5A. 3-(5-Bromopyridin-2-yl)prop-2-yn-1-ol \=N OH

Et ₃ N (33.2 ml , 240 mmol). The solution was degassed under Ar (Ar sparged 3 times), after which (Ph ₃ P) ₂ PdCl ₂ (2.96 g, 4.22 mmol) and CuI (0.804 g, 4.22 mmol) were added. The reaction mixture was stirred at room temperature under Ar for 14 h, after which the mixture was filtered through a pad of Celite®, which was washed with EtOAc (3x50 ml). The combined filtrates were concentrated in vacuo. The residue was subjected to chromatography (SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound as a white solid (16.6 g, 74% yield).

1Н NMR (400 MHz, CD3OD) δ 8.60 (d, J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 4.41 (s , 2H).

5V. (4-(5-Bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

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To a degassed (purged 3 times with Ar) solution of 5A (1.9 g, 8.40 mmol) in dioxane (42.0 ml) was added chloro(pentamethylcyclopentadienyl)-bis-(triphenylphosphine)ruthenium(II) (0.402 g, 0.504 mmol). The mixture was degassed under Ar (3 times), after which TMSCH2N3 (1.87 mL, 12.6 mmol) was added. The reaction mixture was stirred at 50°C for 15 h under Ar, then cooled to room temperature and concentrated in vacuo. The oily crude product was dissolved in THF (90 ml) and cooled to 0°C. TBAF (5.40 ml of a 1.0 M solution in THF; 5.40 mmol) was added and the reaction mixture was stirred at 0°C for 10 min, after which solid NaHCO ₃ (4 g) was added. The reaction mixture was stirred for 30 minutes at room temperature and then filtered. The filtrate was concentrated in vacuo. The residue was subjected to chromatography (SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes, 20 min) to give the title compound (1.30 g, 4.59 mmol, 102% yield) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.49 (dd, J=2.3, 0.7 Hz, 1H), 8.08 (dd, J=8.5, 0.6 Hz, 1H), 7.83 (dd, J=8.5, 2.2 Hz, 1H), 6.16 (t, J=6.9 Hz, 1H), 4.68 (d, J=6.9 Hz, 2H), 3.95 (s, 3H).

5C. 5-Bromo-2-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine

To a stirred solution of the compound of example 5B (300 mg, 1.15 mmol) in dry CH ₂ Cl ₂ (8 ml) was added PBr ₃ (0.21 ml, 2.23 mmol) and the resulting solution was stirred at 0°C for 45 min. The reaction was then quenched with water (20 ml), extracted with EtOAc (2x20 ml) and the combined organic extracts washed with brine (25 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (250 mg, 67%) as yellow oily liquid.

LCMS [M+H]+ = 329.9.

1H NMR (300 MHz, CDCI3) δ 8.64 (d, J=2.10 Hz, 1H), 8.14 (dd, J=0.90, 8.56 Hz, 1H), 7.90 (dd, J=2.40, 5.70 Hz, 1H), 5.18 (s, 2H), 4.13 (s, 3H).

5D. 2-(5-(Azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-5-bromopyridine

To a solution of the compound from example 5C (220 mg, 0.66 mmol) in dry DMF (2.5 ml) was added NaN ₃ (86 mg, 1.33 mmol) and the resulting solution was stirred at 70°C for 16 h, then cooled to room temperature and poured into water (25 ml). The precipitated solid was filtered off, washed with water (5 ml) and dried in vacuo to give the title compound (162 mg, 82%) as a white solid.

LCMS [M+H]+ = 296.0.

1H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J=0.8, 2.4 Hz, 1H), 8.18 (dd, J=2.4, 8.4 Hz, 1H), 8.06 (dd, J=0.8, 8.6 Hz, 1H), 5.10 (s, 2H), 4.11 (s, 3H).

5E. tert-Butyl ((4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)carbamate

Ph ₃ P (178 mg, 0.680 mmol) and water (1 ml) were added to a solution of the compound of example 5D (100 mg, 0.34 mmol) in THF (3 ml) under N2, and the resulting solution was stirred at room temperature for 16 h. To this reaction mixture was added NaOH (34 mg, 0.85 mmol) followed by (Boc) ₂ O (0.10 ml, 0.48 mmol) and the reaction mixture was stirred at room temperature for another 16 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2x20 ml). The combined organic extracts were washed with brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (100 mg, 80%) as a white solid.

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LCMS [M+H]+ = 368.2.

‘H NMR (300 MHz, CDC13) δ 8.67 (d, J=2.1 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.4 Hz, 1H),

5.98-5.99 (m, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.21 (s, 3H), 1.41 (s, 9H).

5F. tert-Butyl ((1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H1,2,3- triazol-5-yl)methyl)carbamate

XX o. χ in and / NHBoc

N-N

To a solution of the compound from example 5E (50 mg, 0.136 mmol) in dioxane (5 ml) was added bis-(pinacolato)diborone (51.7 mg, 0.204 mmol) and KOAc (27 mg, 0.27 mmol). The reaction mixture was purged with N2 for 5 min, after which 1,1'-bis-(diphenylphosphino)ferrocenepalladium(II) dichloride complex in DCM (6 mg, 0.006 mmol) was added. The reaction mixture was stirred at 90°C for 16 h, then cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude title compound (70 mg) as a brown liquid. LCMS: [M+H] ⁺ =416.0. This crude product was used in the next reaction without further purification.

5G. tert-Butyl ((4-(5-hydroxypyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)carbamate

To a stirred solution of the compound of Example 5F (70 mg, 0.722 mmol), in THF (5 ml) and water (1.5 ml) was added sodium perborate monohydrate (41 mg, 0.407 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with water (20 ml). This mixture was extracted with 10% MeOH in CHCl ₃ (2x10 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was chromatographed (12 g Redisep® SiO ₂ column eluting with 3% MeOH in CHCl ₃ ) to give the title compound (40 mg, 96%) as a pale yellow liquid. LCMS [M+H] ⁺ = 306.2. This crude product was used without further purification in the next reaction.

5N. (1S,3S)-Ethyl 3-((6-(5-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4yl)pyridin-3-yl) hydroxy)cyclohexanecarboxylate

To a solution of the compound from example 5G (1.80 g, 5.90 mmol) in THF (35 ml) was added successively di-tert-butyl azodicarboxylate (4.07 g, 17.7 mmol), Ph ₃ P (4.64 g, 17.7 mmol) and (1S,3R)-ethyl-3hydroxycyclohexanecarboxylate (synthesized according to a similar procedure described in US2007/0197788A1, 1.52 g, 8.84 mmol) under N2 atmosphere. The reaction solution was stirred at 60°C for 16 h, then cooled to room temperature and concentrated in vacuo. The crude product was chromatographed (24 g SiO ₂ , 40% EtOAc in hexanes) to give the title compound (1.9 g, 70%) as a pale yellow solid.

LCMS [M+H] ⁺ = 460.1.

'H NMR (300 MHz, CDCI3) δ 8.30 (d, J=2.1 Hz, 1H), 8.15 (d, J=5.4 Hz, 1H), 7.34 (dd, J=2.4, 6.5 Hz, 1H), 6.13 ( s, 1Н), 4.71 (s, 1Н), 4.58 (d, J=1.5 Hz, 2Н), 4.20 (s, 3Н), 4.12 (q, J=3.0 Hz, 2Н), 2.80-2.82 (m, 1Н ), 2.022.05 (m, 1Н), 1.84-1.99 (m, 3Н), 1.56-1.79 (m, 4Н), 1.41 (s, 9Н), 1.26 (t, J=1.2 Hz, 3Н).

5I. (1S,3S)-Ethyl 3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate

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To a stirred solution of Example 5H (1.90 g, 4.13 mmol) in CH2C12 (50 ml) was added HCl in dioxane (10.3 ml of a 4 M solution, 41.3 mmol) and the resulting solution was stirred at room temperature for over 12 hours. The reaction mixture was concentrated in vacuo to give the title compound (1.25 g, 84%) as a pale yellow solid. LCMS [M+H] ⁺ =360.0. This crude product was used without further purification in the next reaction.

5J. Ethyl (1 S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin3-yl)oxy )cyclohexane-1-carboxylate

To a stirred solution of the compound of Example 5I (30 mg, 0.083 mmol) in CH ₂ Cl ₂ (5 mL) under N2 was added n-butyl chloroformate (78 μL, 0.83 mmol) and the resulting solution was stirred at room temperature for 16 h The reaction mixture was concentrated in vacuo and the crude product was chromatographed (12 g SiO ₂ , isocratic elution with 27% EtOAc in hexanes) to give the title compound (30 mg, 82%) as a pale yellow liquid.

LCMS [M+H] ⁺ = 432.2.

Example 5

To a stirred solution of the compound from example 5J (30 mg, 0.046 mmol) in THF (4 ml) and MeOH (1 ml) was added a solution of L1OH-H2O (2 mg, 0.093 mmol) in water (1.5 ml) and the resulting solution was stirred at room temperature for 16 hours the Reaction mixture was diluted with water (20 ml) and washed with Et ₂ O (20 ml). The aqueous layer was neutralized with aq. 1.5n. HCl (2 ml) and extracted with 5% MeOH in CHCl ₃ (25 ml). The organic layer was washed with brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (Sunfire C18, 150x19 mm; 5 µm; mobile phase A: 10 mM aq. NH ₄ OAc (pH: 4.5); mobile phase B: MeCN, flow rate: 15 ml/min ; time (min)/%B: 0/20, 25/60; retention time: 15.19 min) to give the title compound (6 mg, 32%) as a white solid.

LCMS [M+H] ⁺ = 432.0.

1H NMR (400 MHz, CD3OD) δ 8.40 (br. s., 1H) 8.00 (d, J=8.8 Hz, 1H) 7.53 (dd, J=8.8, 2.7 Hz, 1H), 4.704.80 (m, 1H ) 4.58 (s, 3H) 4.20 (s, 3H) 4.03 (t, J=6.6 Hz, 2H) 2.77-2.88 (m, 1H) 1.87-2.15 (m, 3H) 1.45-1.86 (m, 6H) 1.23- 1.44 (m, 2H) 0.92 (t, J=7.3 Hz, 3H).

hLPA1 IC ₅₀ = 96 nM.

In table. 1 shows compounds according to additional examples, which were obtained using the same synthetic method as described in this document.

Table 1

Note. No. Structure and title Analytical and biological data Method 6 1G Ν—Ν H ° A/ \ (1S, 3 S)-3 -((6-(5 -((((cyclopentyloxy) carbonyl)amino)methyl)-1-methyl-1H1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 444.2; Ή NMR (400 MHz, CD ₃ OD): δ 8.38 (s, 1H), 7.97 (d, J = 7.20 Hz, 1H), 7.51 (d, J = 8.80 Hz, 1H), 5.02-5.06 (m, 1H ), 4.72-4.78 (m, 3H), 4.17(s, 3H), 2.722.78 (m, 1H), 2.01-2.09 (m, 1H), 1.90-1.98 (m, 3H), 1.52-1.78 (m , 13H); hLPAi IC ₅₀ = 84 hM. Example 3

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7 ,A^A,. /° ⁿ Г mA/ \ (1 S,3 S)-3 -((6-(5 -((((cyclopropylmethoxy)carbonyl)amino)methyl)-1 methyl-1 Η-1,2,3-triazo l-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 444.2; ³ H NMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.40 Hz, 1H), 7.47 (d, J = 8.80 Hz, 2H), 4.72-4.78 (m, lH), 4.57(s, 2H) ,4.19(s, 3H), 3.88 (d, J = 7.20 Hz, 2H), 2.79-2.81 (m, 1H), 2.56 (s, 3H), 1.97-2.11 (m, 1H), 1.79-1.97 (m , 3H), 1.65–1.72 (m, 4H), 0.50–0.55 (m, 2H), 0.26 (d, J = 4.80 Hz, 2H); hLPAi IC ₅₀ = 47 hM. Example 3 8 /HE PI N-N N O \ (18.38)-3-((6-(5-(((((3,5-difluorobenzyl)oxy)carbonyl)amino)methyl)-1 methyl-1 Η-1,2,3-triazo l- 4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 516.1; 'HNMR (400 MHz, CD3OD): δ 7.84 (d, J = 8.80 Hz, 1H), 7.59 (d, J = 8.80 Hz, 2H), 4.99 (s, 2H), 4.65 (s, 2H), 4.06 ( s, 3H), 2.63-2.72 (m, 1H), 2.49 (s, 3H), 1.97-2.07 (m, 1H), 1.79-1.97 (m, 3H), 1.54-1.72 (m, 4H); hLPAi IC ₅₀ =5hM. Example 1 9 -DA / ° ⁿ \ (1 S,3 S) -3 - ((6- ( 1 -methyl-5 - (((phenetoxycarbonyl) amino) methyl) -1H-1,2,3triazol-4-yl) pyridine -3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 480.0; Ή NMR (400 MHz, DMSOJ ₆ ) δ 8.35 (d, 7=2.93 Hz, 1 Η) 7.98 (d, 7=8.80 Hz, 1 Η) 7.50-7.54 (m, 1 Η) 7.187.29 (m, 5 Η) 4.78 - 4.80 (m, 1Η) 4.73 (d, 7=5.38 Hz, 2 Η) 4.10 - 4.16 (m, 2 Η) 4.03 (s, 3 Η) 2.78 - 2.87 (m, 2 Η) 2.64 - 2.68 (m, 1 H) 1.95 (s, 1H) 1.83 (br. S., 4 H) 1.51 - 1.68 (m, 3 H); hLPAi IC ₅₀ = 672 hM. Example 1 10 A^A^ / He? _g At NN^ Η O DD (1 S,3 S) -3 - ((6-( 1 -methyl-5 - (((((R) -1 - LCMS, [M + H] ⁺ = 480.2; Ή NMR (400 MHz, DMSOό/β) δ 8.35 (d, 7=3.18 Hz, 1 H) 7.97 (d, 7=8.80 Hz, 1 H) 7.49 - 7.66 (m, 2 H) 7.32 (br. s. ,4H)5.67 (d, 7=6.60 Hz, 1 H) 4.76 (br. s., 1 H) 4.76 (br. s., 2 H) 4.02 (s, 3 H) 2.68 (br. s., 1 H) 1.74 -1.93 (m,4H) 1.50 - 1.68 (m, 4H) 1.42 (d, 7=6.60Hz, 3H); Example 1

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phenylethoxy)carbonyl)amino)methyl)1H-1,2,3-triazol-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid hLPAi 1C ₅₀ = 104 nM. eleven /HE N-N H ° \ (18.38)-3-((6-(5-(((((3-fluorobenzyl)oxy)carbonyl)amino)methyl)-1 methyl-1 Η-1,2,3-triazo l-4- yl) -2-methylpyridin-3-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 498.1; Ή NMR (400 MHz, CD3OD): δ 7.84 (d, J = 8.00 Hz, 1H), 7.45 (d, J = 8.40 Hz, 1H), 7.32-7.37 (m, 1H), 7.01-7.15 (m, 3H ), 5.10 (s, 2H), 4.74-7.79 (m, 3H), 4.16 (s, 3H), 2.78-2.84 (m, 1H), 2.52 (s, 3H), 2.10-2.14 (m, 1H), 1.92-1.98 (m, 3H), 1.63-1.78 (m, 4H); hLPAi IC ₅₀ =6hM. Example 1 12 /HE N-N H O \ (1 S,3 S)-3 -((6-(5 -(((((3-fluorobenzyl) oxy)carbonyl)amino)methyl)-1-methyl1H-1,2,3-triazol-4-yl )pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 484.2; ΉΉΜΡ (400 MHz, CD3OD): δ 7.99 (d, J = 7.60 Hz, 1H), 7.52 (d, J = 8.00 Hz, 1H), 7.32-7.37 (m, 1H), 7.01-7.14 (m, 3H) , 5.08 (s, 2H), 4.74-4.79 (m, 3H), 4.19 (s, 3H), 2.81-2.84 (m, 1H), 2.01-2.11 (m, 1H), 1.90-2.00 (m, 3H) , 1.62-1.79 (m, 4H); hLPAi IC ₅₀ = 23 hM. Example 1 13 /OH A ...... Ν-Ν Η O \ (1 S,3 S)-3 -((6-(5 -((((hexyloxy)carbonyl)amino)methyl)-1 -methyl- 1H1,2,3-triazol-4-yl)pyridine-3 -yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.2; ΉΉΜΡ (400 MHz, CD ₃ OD) δ 8.40 (d, 7=3.0 Hz, 1 Η) 8.00 (d, 7=8.5 Hz, 1 Η) 7.53 (dd, 7=8.9, 2.8 Hz, 1 Η) 4.75 ( s, 1 H) 4.73(m 2H) 4.20 (s, 3 Η) 4.02 (t, 7=6.5 Hz, 2 Η) 2.82 (d, 7=4.5 Hz, 1 Η) 2.08 (br. s., 1H) 1.93 (br. s., 3H) 1.66 - 1.77 (m, 6H) 1.31 (d, 7=3.5 Hz, 6 H) 0.90 (s, 3H); hLPAi IC ₅₀ = 428 nM. Example 3

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14 L /OH / 1Г u Ν-Ν _χ / ⁰ (1 S,3 S)-3 -((6-(5 -(((butoxycarbonyl) (methyl)amino)methyl) -1 -methyl-1 Η-1 ,2,3 triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.2; Ή NMR (400 MHz, CD ₃ OD) δ 8.37 (br. s., 1 Η) 7.98 (d, 7=9.04 Hz, 1 Η) 7.48 -7.56 (m, lH) 5.19(s, 2H), 4.92 ( m, 2H), 4.80 (m 1H) 4.07-4.17 (m, 3H), 2.82 (s, 3 H), 2.05 (d, 7=13.05 Hz, 2 H), 1.601.81 (m, 8H), 1.32 -1.45 (m, 2H), 1.41 (br. s., 1 H), 0.88-1.01 (m, 3 H); hLPAi IC ₅₀ = 1024 nM. Example 2 15 /HE ? if V _...... -1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.4; 'HNMR (400 MHz, CD3OD) δ 8.37 (d, 7=3.01 Hz, 1 Η) 7.98 (d, 7=9.04 Hz, 1 Η) 7.53 (dd, 7=9.04, 3.01 Hz, 1 Η) 5.19 (s , 2 H)4.9(m 2H)4.7(mlH) 4.05-4.16 (m, 3H) 2.82 (s, 3H) 2.07 (br. s., 3H) 1.92 (br. s.,2H) 1.57 - 1.82 (m, 6 H) 1.251.44 (m, 5 H) 0.83 - 1.00 (m, 3H); hLPAi IC ₅₀ = 130 nM. Example 2 16 DD/OH/g /ttd) \ (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 (((phenetoxycarbonyl)amino)methyl)1H-1,2,3-triazo l-4-yl)pyridine -3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 494.1; 1HNMR (400 MHz, CD3OD): δ 7.83 (d, J = 8.80 Hz, 1H), 7.45 (d, J = 8.40 Hz, 1H), 7.13-7.17 (m, 5H), 4.77-4.77 (m, 1H) , 4.69 (s, 2H), 4.24 (t, J = 6.80 Hz, 2H), 4.15 (s, 3H), 2.79-2.88 (m, 3H), 2.50 (s, 3H), 2.092.17 (m, 1H ), 1.89-1.97 (m, 3H), 1.55-1.78 (m, 4H); hLPAi IC ₅₀ = 32 hM. Example 1 17 DD /ON 9 f D „b N-N H O \ (18.38)-3-((6-(5-(((((2,5-difluorobenzyl)oxy)carbonyl)amino)methyl)-1 methyl-1 Η-1,2,3-triazo l- 4-yl) -2 - LCMS, [M + H] ⁺ = 516.1; 'HNMR (400 MHz, CD3OD): δ 7.84 (d, 7 = 8.80 Hz, 1H), 7.46 (d,7 = 8.80 Hz, 2H), 5.14(s, 2H), 4.72-4.84 (m, 3H), 4.17(s, 3H), 2.76-2.82 (m, 1H), 2.52 (s, 3H), 1.97-2.11 (m, 1H), 1.79-1.97 (m, 3H), 1.65-1.72 (m, 4H); hLPAi IC ₅₀ =7hM. Example 1

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methylpyridin-3-yl)oxy)cyclohexane1-carboxylic acid 18 G ° MAv N-N^ N ° VT (1 S,3 S)-3 -((2-methyl-6-( 1 -methyl-5 -(((((R)- 1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 494.1; Ή NMR (400 MHz, CD3OD): 5 7.71 (d, A = 8.40 Hz, 1H), 7.34 (d, J = 8.80 Hz, 1H), 7.14-7.18 (br, 5H), 5.59-5.63 (m, 1H ), 4.63-4.74 (br, 3H), (s, 2H), 3.97 (s, 3H), 2.69-2.70 (br, 1H), 2.44 (s, 3H), 1.97-2.09 (br, 1H), 1.81 -1.97 (w, 4H), 1.50-1.78 (m, 7H), 1.32-1.36 (t, W); hLPAi 1C ₅₀ = 12 nM. Example 1 19 Λ___ \ YUN T g Ad Ν-Ν H ⁰ \ (1 S,3 S) -3 - ((2-methyl-6- ( 1 -methyl-5 - (((((3 methylbenzyl) oxy) carbonyl) amino )methyl)-1H-1,2,3-triazol-4yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 494.1; Ή NMR (400 MHz, CD3OD): 5 7.82 (d, A = 8.00 Hz, 1H), 7.44 (d,A = 8.40 Hz, 1H), 4.77-7.48 (t, 3H), 5.03 (s, 2H), 4.14(s, 3H), 2.76-2.81 (t, 1H), 2.50 (s, 3H), 2.30(s, 3H), 1.972.09 (t, 1H), 1.81-1.97 (t, 3H), 1.59- 1.78 (t, 4H); hLPAi 1C ₅₀ =4nM. Example 1 20 „LA / ON / G G° _ Ν-Ν N O \ (1 S,3 S)-3 -((6-(5 -((((hexyloxy) carbonyl)amino)methyl)-1 -methyl- 1H- 1,2,3-triazol-4-yl)-2-methyl-pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid acid LCMS, [M + H] ⁺ = 474.1; Ή NMR (400 MHz, CD3OD): 5 7.83 (d, A = 8.40 Hz, 1H), 7.45 (d, A = 8.80 Hz, 1H), 4.77-4.79 (t, 1H), 4.76 (s, 2H), 4.16(s, ZH), 4.02 (t, А = 6.80 Hz, 2Н), 2.80-2.82 (t, 1Н), 2.52 (s, ЗН), 2.09-2.17 (t, 1Н), 1.89-1.97 (t, 3H), 1.55–1.78 (t, 6H), 1.21–1.29 (t, 6H), 0.84 (t, A = 2.00 Hz, 3H); hLPAi 1C ₅₀ = ZnM. Example 3

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21 A, /° Η J° A^D yLgcha \ (1 S,3 S)-3 -((6-(5 -((((2-methoxy- ethoxy)carbonyl)amino)methyl)-1 -methyl- 1 Η-1,2,3 -triazo l-4 -yl) -2- methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid LCMS, [M + H] ⁺ = 448.1; Ή NMR (400 MHz, DMSOd6): δ 7.83 (d, J = 8.40 Hz, 1H), 7.61-7.64 (m, 1H), 7.48 (d, J = 9.60 Hz, 1H), 4.764.78 (m, 3H ), 4.05-4.08 (m, 5H), 3.45-3.53 (m, 2H), 3.2 (s, 3H), 2.59-2.62 (m, 1H), 2.44 (s, 3H), 1.99-2.05 (m, 1H ), 1.75-1.90 (m, 3H), 1.48-1.63 (m, 4H); hLPAi IC ₅ o= 1615 nM. Example 3 22 sDZuOn o n 1 I°ΟΛΑ,\Π (1 S,3 S) -3 -((2-methyl-6-( 1 -methyl-5 ((((peopentyloxy)carbonyl)amino)methyl)- 1H-1,2,3-triazol-4-yl )pyridine3 -yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] = 460.1; 'HNMR (400 MHz, CD3OD): δ 7.85 (d, J = 8.40 Hz, 1H), 7.47 (d, 7=8.40 Hz, 1H), 4.77-4.79 (m, 1H), 4.76 (s, 2H), 4.18 (s, 3H), 3.76 (s, 2H), 2.80-2.82 (m, 1H), 2.55 (s, 3H), 2.10-2.17 (m, 1H), 1.89-1.97 (m, 3H), 1.62- 1.78 (m, 4H), 0.90 (s, 9H); hLPAi IC ₅ o=35hM. Example 3 23 A___U. .OH G \/k ⁰ x 1 I O Ν-Ν Η ° \ (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 ((((pentyloxy) carbonyl) amino )methyl)1H-1,2,3-triazol-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.4; Ή NMR (400 MHz, CD3OD): δ 7.83 (d, 7 = 8.80 Hz, 1H), 7.45 (d, 7= 8.80 Hz, 1H), 4.77-4.79 (m, 1H), 4.74 (s, 2H), 4.16 (s, 3H), 4.02 (t, J = 7.60 Hz, 2H), 2.80-2.82 (m, 1H), 2.53 (s, 3H), 2.09-2.17 (m, 1H), 1.89-1.97 (m, 3H), 1.55-1.78 (m, 6H), 1.23-1.31 (m, 4H), 0.88 (t, 7 = 7.20 Hz, ZN); hLPAi IC ₅₀ =3 nM. Example 3 24 /HE Ν-Ν Η O \ LCMS, [M + H] = 432.1; SNMR (400 MHz, CD ₃ OD): 400 MHz, MeOD: δ 7.83 (d, 7 = 8.80 Hz, 1H), 7.45 (d, 7 = 8.80 Hz, 1H), 4.77-4.79 (m, 1H), 4.74 (s, 2H), 4.16(s, 3H), 3.98 (t, J = 6.40 Hz, 2H), 2.80-2.82 (m, 1H), 2.53 (s, 3H), 2.09-2.17 (m, 1H), 1.89-1.97 (m, 3H), Example 3

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(1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 (((propoxycarbonyl)amino)methyl) -1H1,2,3-triazol-4-yl)pyridin-3 - yl) hydroxy)cyclohexane-1-carboxylic acid 1.55-1.78 (br, 6H), 0.90 (t, 7 = 7.20 Hz, ZN); hLPAi 1C ₅₀ = 160 nM. 25 /HE N-N^ H° (18.38)-3-((6-(5-(((isobutoxycarbonyl)amino)methyl)-1-methyl-1H1,2,3-triazol-4-yl)-2-methyl-pyridin-3yl )oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.0; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.82 (d, 7=7.9 Hz, 1H), 7.48 (d, 7=8.5 Hz, 1H), 4.90 - 4.64 (m, 3H), 4.04 (s, 3H), 3.56 (d, 7=14.0 Hz, 2H), 2.44 (br. s., ZN), 2.07-1.39 (m, YuN), 0.82 (br. s., 6H); hLPAi IC ₅₀ =51 hM. Example 3 26 J'/, /OH NN\ H ⁰ (1 S,3 S)-3 -((6-( 1 -methyl-5 -((((neopentyloxy)carbonyl)amino) methyl) - 1H-1,2, 3-triazol-4-yl)pyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.1; 'HNMR (400 MHz, CD ₃ OD) δ 8.40 (br. S., 1 H) 7.99 (d, 7=9.05 Hz, 1 H) 7.53 (dd, 7=8.80, 2.93 Hz, 1 H) 4.76 (br . S., lH)4.19(s, 3H)3.75 (s, 2H) 2.772.89 (m, 1H) 1.87-2.17 (m,4H) 1.58 - 1.85 (m, 4H) 0.90 (s, 9H ); hLPAi IC ₅₀ = 44 hM. Example 3 27 F, /OH X... N-N H O \ (18.3 8)-3-((6-( 1 -methyl-5 - ((((pentyloxy)carbonyl)amino)methyl)- 1H-1,2,3-triazol-4-yl)pyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.1; SNMR (400 MHz, CD ₃ OD) δ 8.40 (br. Sn 1 H), 8.00 (d, 7=8.80 Hz, 1 H), 7.53 (dd, 7=8.80, 2.69 Hz, 1 H), 4.74 ( br. S, 3H), 4.20 (s, 3H), 4.02 (t, 7=6.60 Hz, 2 H), 2.77 - 2.88 (m, 1 H), 1.87-2.15 (m, 4 H), 1.441.85 (m, 6 H), 1.31 (br. S., 4 H), 0.92 (t, 7=7.34 Hz, 3 H); hLPAi IC ₅₀ = 16 hM. Example 3

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28 / ^0H \ / U o II 1 N0 I 0 ⁿ / ^ ⁿ ^ _o -ZA N-NH ⁰ \ (1 S,3 S) -3 - ((6- (5 - ((((cyclopentyloxy) carbonyl) amino)methyl) -1 -methyl1 Η-1,2,3 -triazo l-4 -yl) -2methylpyridin-3-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 458.2; Ή NMR (400 MHz, CD ₃ OD): 5 7.82 (d, J =8.40 Hz, 1H), 7.45 (d, J =8.80 Hz, 1H), 5.02-5.05 (m, 1H), 4.73-4.77 (m , 1H), 4.56 (s, 2H), 4.15 (s, 3H), 2.72-2.77 (m, 1H), 2.53 (s, 3H), 2.302.18 (m, 1H), 1.91-1.98 (m, 3H ), 1.52-1.78 (m, 12H); hLPAi IC ₅₀ = 18 nM. Example 3 29 /He 9f R 140 N O (1 S,3 S)-3 -((6-(5 -(((isobutoxycarbonyl)amino)methyl)-1 -methyl- 1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 432.2; 1H NMR (400 MHz, CD ₃ OD): 5 8.38 (s, 1H), 7.98 (d, J= 8.00 Hz, 1H), 7.51 (dd,7 = 2.40, 8.80 Hz, 1H), 4.78-4.79 (m , 1H), 4.72 (s, 2H), 4.17(s, 3H), 3.79 (d, J =6.80 Hz, 2H), 2.75-2.79 (m, 1H), 2.01-2.06 (m, 1H), 1.87- 2.00 (m, 3H), 1.61-1.78 (m, 5H), 0.88 (d, J=6.40 Hz, 6H); hLPAi IC ₅₀ = 179 nM. Example 3 thirty /OH G 7 ° N-N N O \ \ (18.38)-3-((6-(5-(((tert-butoxycarbonyl)amino)methyl)-1 methyl-1 Η-1,2,3-triazo l-4-yl) -2 methylpyridin-3- yl)oxy)cyclohexane 1-carboxylic acid LCMS, [M + H] ⁺ = 446.4; ΉΑΜΡ (400 MHz, CD ₃ OD):5 7.83 (d, J =8.80 Hz, 1H), 7.45 (d, 7=8.40 Hz, 1H), 4.79-4.81 (m, 1H), 4.68 (s, 2H) , 2.76-2.79 (m, 1H), 2.09-2.12 (m, 1H), 1.91-1.98 (m, 3H), 1.63-1.78 (m, 4H), 1.41 (s, 9H); hLPAi IC ₅₀ = 120 nM. Example 3 31 /HE ? 1G A... N0 N O F LCMS, [M + H] ⁺ = 500.3; Ή NMR (500 MHz, DMSOd ₆ ) 5 8.35 (br s, 1H), 7.97 (br d, 7=8.7 Hz, 1H), 7.63-7.50 (m, 2H), 4.87 -4.70 (m, 3H), 4.05 (s, 3H), 3.83 (brd, 7=5.1 Hz, 2H), 2.70 -2.61 (m, 1H), 2.39 - 1.43 (m, 11H), 0.94 (br d, 7=5.1Hz, ZN); Example 1

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(1 S,3 S)-3 -((6-( 1 -methyl-5 -((((4,4,4trifluoro-2-methylbutoxy)carbonyl) amino)methyl) -1H-1,2,3- triazol-4yl)pyridin-3 -yl)oxy)cyclohexane carboxylic acid (Mixture of diastereomers at -CH3) hLPAi 1C ₅₀ = 102 nM. 32 "L. „°n L ° NN^ H ⁰ y-y / _F F (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 ((((4,4,4-trifluoro -2-methylbutoxy)carbonyl)amino)methyl) -1 Η-1,2,3 triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (Mixture of diastereomers at -CH3) LCMS, [M + H] ⁺ = 514.1; Ή NMR (400 MHz, CDC1 ₃ ) 5 8.07 (d, 7=8.8 Hz, 1H), 7.69 (brd, 7=8.1 Hz, 1H), 4.86 - 4.77 (m, 1H), 4.60 (s, 2H), 4.20 (s, 3H), 4.02-3.92 (m, 2Н), 2.68 (s, ZN), 2.30 1.62 (t, ST), 1.06 (d, 7=6.6 Hz, ZN); hLPAi 1C ₅₀ = 69 nM Example 1 33 YES. / ^He / g £ ° Pl NN^ H ° X-T (1 S,3 S)-3 -((6-(5 -((((cyclobutylmethoxy)carbonyl)amino)methyl)-1 methyl-1 Η- 1,2,3-triazo l-4-yl) -2 methylpyridin-3-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 458.0; Ή NMR (500 MHz, DMSOd ₆ ) □ 7.81 (d, 7=8.4 Hz, 1H), 7.58 (br. s., 1H), 7.47 (d, 7=8.5 Hz, 1H), 4.81 4.67 (t, 3H) , 4.03 (s, 3H), 3.94–3.85 (t, 2H), 2.662.56 (t, 1H), 2.47–2.37 (t, 4H), 2.03–1.41 (t, 14H); hLPAi 1C ₅₀ = P nM. Example 3 34 A D / ^0H C g 5 NN H ⁰ \ (1 S,3 S) -3 - ((6- (5 - ((((benzyloxy) carbonyl) amino) methyl) -1 -methyl- 1H1,2,3 -triazo l-4 -yl) -2 -methylpyride in-3 yl)oxy)cyclohexane-1 -carboxylic acid LCMS, [M-H] ⁺ = 480.1; Ή NMR (500 MHz, DMSOd ₆ ) 5 7.81 (d, 7=8.3 Hz, 1H), 7.68 (br. s., 1H), 7.47 (d, 7=8.4 Hz, 1H), 7.30 (br. s., 5Н), 5.01 (br. s., 2Н), 4.82 4.70 (t, GL), 4.03 (br. s., GL), 2.61–2.55 (t, 1Н), 2.41 (s, GL), 2.02–1.45 (t, 8H); hLPAi 1C ₅₀ =9nM, in vivo histamine emergency assay in CD-1 mice: -96% histamine at 1 mg/kg of the compound of Example 34. Example 3

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35 D___J/,, .OH _G vX ⁰ g,° 9 n4 J/ NN^ 1° (18.38)-3-((6-(5-((((benzyloxy)carbonyl)(methyl)amino)methyl) -1 methyl-1 Η-1,2,3 -triazo l-4-yl) -2 methylpyridin-3 -yl)oxy) cyclohexanecarboxylic acid LCMS, [M + H] ⁺ = 494.0; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.86 - 7.69 (m, 1H), 7.52 -7.26 (m, 6H), 5.20 5.06 (m, 4H), 4.81 -4.70 (m, 1H), 3.97 (br. s ., 3H), 3.32 (br. s., 3H), 2.66 - 2.59 (m, 1H), 2.40 (br. s., 3H), 2.05 1.41 (m, 8H); hLPAi IC ₅₀ = 56 hM. Example 2 36 /OH ϋ ° N-N _χ 1 0 (1 S,3 S)-3 -((6-(5 -(((butoxycarbonyl) (methyl)amino)methyl)-1 -methyl- 1H-1,2, 3triazol-4-yl)-2-methyl-pyridin-3 yl)oxy)cyclohexane carboxylic acid LCMS, [M + H] ⁺ = 457.9; Ή NMR (500 MHz, DMSOde) δ 7.84 (d, 7=7.9 Hz, 1H), 7.48 (d, 9=8.2 Hz, 1H), 5.11 (br. s., 2H), 4.81 -4.71 (m, 1H ), 3.99 (s, 5H), 2.66-2.56 (m, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 2.03 - 1.20 (m, 12H), 0.93 - 0.80 (m, 3H); hLPAi IC ₅₀ = 19 nM. Example 2 37 "D___U, is he? at \ (1 S,3 S)-3 -((6-(5 -((((3,3-dimethylbutoxy)carbonyl)amino)methyl)-1-methyl- 1H-1,2,3-triazol4-yl) -2-methylpyridin-3-yl)oxy) cyclohexanecarboxylic acid LCMS, [M + H] ⁺ = 474.0; Ή NMR (500 MHz, DMSOά ₆ )δ7.81 (d, 9=8.1 Hz, 1H), 7.54 -7.39 (m, 2H), 4.804.65 (m, 3H), 4.09 -3.90 (m, 5H), 2.60 - 2.55 (m, 1H), 2.42 (s, 3H), 2.01 - 1.35 (m, 10H), 0.83 (br. s., 9H); hLPAi IC ₅₀ = 12 nM Example 3 38 -D D, /OH 9= N-N H O \ LCMS, [M + H] ⁺ = 486.0; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.82 (d, 9=8.4 Hz, 1H), 7.55 (br. sn 1H), 7.47 (d, 9=8.6 Hz, 1H), 4.82 -4.67 (m, 3H ), 4.03 (s, 3H), 3.89 (d, 9=4.3 Hz, 1H), 2.67 2.57 (m, 1H), 2.46 - 2.32 (m, 4H), 2.04 - 1.38 (m, 13H), 1.07 (br .s.,3H), 0.96 (br.s., Example 3

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(lS,3S)-3-((6-(5-(((((3,3dimethylcyclobutyl)methoxy)carbonyl)amino)methyl)-1-methyl- 1H-1,2,3triazol-4-yl)- 2-methylpyridin-3yl)oxy)cyclohexanecarboxylic acid ZN); hLPAi 1C ₅₀ = 19 nM. 39 / ^0H T 1H L Ν—N H ^{0 1} 2,3-triazol-4-yl) phenoxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 443.1; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.79 (br. s., 1H), 7.64 (d, 7=7.3 Hz, 2H), 7.03 (d, 7=8.2 Hz, 2H), 4.71 -4.63 (m, 1H), 4.41 (d, 7=4.6 Hz, 2H), 4.08 -3.94 (m, 5H), 2.67 -2.56 (m, 1H), 1.941.37 (m, 10H), 0.74 - 0.60 (m, 1H) , 0.44–0.32 (m, 2H), 0.09–0.01 (m, 2H); hLPAi IC ₅ o = 457hM. Example 4 40 / ^he 9 1G V.d NN H O \ (±)-trans-3 - (4- (5 - ((((benzyloxy) carbonyl) amino) methyl) -1 -methyl- 1H1,2,3-triazole- 4-yl)phenoxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 465.0; Ή NMR (500 MHz, DMSOd ₆ ) δ 8.04 - 7.92 (m, 1H), 7.65 (brd, 7=8.2 Hz, 2H), 7.41 -7.29 (m, 5H), 7.03 (br d, 7=7.9 Hz, 2H), 5.06 (s, 2H), 4.75 - 4.63 (m, 1H), 4.46 (br d, 7=4.9 Hz, 2H), 4.04 (s, 3H), 2.72 - 2.63 (m, 1H), 2.02- 1.47(m, 8H); hLPAi IC ₅₀ = 664 hM. Example 4 41 '|f z^/k o n ι 1 O N-N^ Η O (1 S,3 S)-3 -((6-(5 -(((butoxycarbonyl) amino)methyl)-1 -methyl- 1H-1,2,3triazol-4-yl)-2-ethylpyridin-3- yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.2; Ή NMR (500 MHz, DMSOde) δ 7.82 (br d, 7=8.5 Hz, 1H), 7.45 (br d, 7=8.9 Hz, 2H), 4.75 (br s, 3H), 4.02 (s, 3H), 3.91 (brs, 1H), 3.64 (br d, 7=15.9 Hz, 2H), 2.81 (q, 7=7.3 Hz, 2H), 2.04-1.97 (m, 1H), 1.84 (brd, 7=12.8 Hz, 1H), 1.81–1.73 (m, 2H), 1.63–1.50 (m, 3H), 1.45 (br s, 3H), 1.28–1.18 (m, 6H), 0.81 (br s, 3H); hLPAi ICso = 8hM. Example 1

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42 ⁰ n η I ο ^Ν Ν-Ν Η Ο^\^\ (1 S,3 S)-3 - ((2-ethyl-6-( 1-methyl-5 (((propoxycarbonyl) amino) methyl) -1H1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.2; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.80 (br d, 7=8.2 Hz, 1H), 7.44 (br d, 7=8.5 Hz, 1H), 4.73 (brd, 7=18.6 Hz, 2H), 4.02 ( s, 2H), 3.96-3.75 (m, 1 OH), 2.80 (q, 7=7.3 Hz, 1H), 1.99 (brd, 7=16.2 Hz, 1H), 1.83 (brd, 7=12.2 Hz, 1H) , 1.80 - 1.70 (m, 1H), 1.62 - 1.50 (m, 2H), 1.46 (br s, 2H), 1.26-1.15 (m, 3H), 0.78 (br s, 2H); hLPAi IC ₅₀ = 788 hM. Example 1 43 G\/L,/OH 9 1f ⁰ ? „p Ν-Ν H ⁰ \ (1 S,3 S) -3 - ((6- (5 - ((((benzyloxy) carbonyl) amino) methyl) -1 -methyl- 1H1,2,3 -triazol -4 -yl) -2 -ethylpyridin-3 yl)oxy)cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 494.4; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.82 (br d, 7=8.2 Hz, 1H), 7.46 (br d, 7=8.5 Hz, 1H), 7.34 - 7.27 (m, 5H), 5.00 (br s, 2H), 4.81 (br s, 2H), 4.76 (br s, 1H), 4.02 (br s, 3H), 3.56 (brs, 1H), 2.8O (br d, 7=7.3 Hz, 2H), 2.63 2.57 (m, 1H), 2.05 - 1.98 (m, 1H), 1.85 (brd,7=12.8 Hz, 1H), 1.81-1.74 (m, 2H), 1.63 - 1.52 (m, 3H), 1.48 (br d, 7=7.6 Hz, 1H), 1.21 (brt, 7=7.2 Hz, ZN); hLPAi IC ₅₀ = 8 hM. Example 1 44 „AL / ^He ° II | N^ N-ν Η ° \ (lS,3S)-3-((6-(5- ((((cyclopentyloxy)carbonyl)amino)methyl)-1-methyl-1 Η-1,2,3-triazole -4 -yl) 2-ethylpyridin-3 -yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 472.1; Ή NMR (500 MHz, DMSOde) δ 7.83 (br d, 7=8.5 Hz, 1H), 7.48 (d, 7=8.9 Hz, 1H), 4.94 (br s, 1H), 4.77 (br s, 3H), 4.04 (s, 3H), 2.91 -2.73 (m, 2H), 2.61 (brt,7=10.5Hz, 1H), 2.O8 - 1.95 (m, 1H), 1.86 (brd, 7=12.2Hz, 1H) , 1.83-1.71 (m, 3H), 1.62 (br d, 7=9.5 Hz, ZN), 1.55 (br s, 3H), 1.51 (brs, 4H), 1.25 (br t, 7=7.3 Hz, 4H) ; hLPAi IC ₅₀ = 37 hM. Example 1 45 А„ DEN γ-\/Α ⁰ Υ 1 I ° ΥγΛΑ/ NN^ H ⁰ LCMS, [M + H] ⁺ = 474.4; Ή NMR (500 MHz, DMSOde) δ 7.84 (br d, 7=8.2 Hz, 1H), 7.49 (br d, 7=8.2 Hz, 2H), 4.77 (br s, 3H), 4.04 (s, 3H), 3.65 (br s, 2H), 2.902.71 (m, 2H), 2.60 (brs, 1H), 2.01 (brd, 7=11.9 Hz, 1H), 1.90 (s, 1H), 1.87-1.72 (m, 3H ), 1.67 - 1.53 (m, 3H), Example 1 (1 S,3 S)-3 -((2-ethyl-6-(1-methyl-5 ((((neopentyloxy)carbonyl)amino)methyl)- 1H-1,2,3-triazol-4-yl )pyridine3-yl)oxy)cyclohexane-1-carboxylic acid 1.50 (brs, 1H), 1.25 (brt, 7=7.5 Hz, ZN), 0.83 (brs, 9H); hLPAi IC ₅₀ = 94 hM. 46 G \ / A, / OH / -γ / k O n 1 N ^ J I o NN ^ Η ⁰ (1 S,3 S) -3 - ((2-ethyl-6- (5 - (((isobutoxy carbonyl) amino)methyl)-1-methyl-1H1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.2; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.84 (br s, 1H), 7.49 (br d, 7=8.5 Hz, 1H), 4.78 (br s, 3H), 4.04 (s, 3H), 3.73 (brd, 7=6.1Hz, 1H),2.83(brd, 7=7.3Hz, 2H),2.61(brt, 7=10.4Hz, 1H), 2.09-1.97(m, 1H), 1.86(brd,7=12.5Hz, 1H), 1.83 - 1.72 (m, 3H), 1.66 - 1.46 (m, 5H), 1.25 (br t, 7=7.2 Hz, 4H), 0.83 (br d, 7=5.8 Hz, 6H); hLPAi IC ₅₀ = 120 hM. Example 1

In table. 2 shows additional examples of compounds that were synthesized using the intermediates described below.

Intermediate 2. 4-Nitrophenyl ((1-propylcyclopropyl)methyl)carbonate

Intermediate 2A. tert-Butyl 1-propylcyclopropane-1-carboxylate

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To a solution of LDA in THF (40 ml of a 0.8M solution; 33.2 mmol) at -78°C was added tert-butyl cyclopropane carboxylate (3.78 g, 26.6 mmol) dropwise over 10 min. The solution was stirred at -78°C for 2 h, after which 1-bromopropane (4.84 ml, 53.2 mmol) was added dropwise over 20 min at -78°C. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight at room temperature, then quenched with saturated aqueous NH4C1 and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was distilled under reduced pressure (20 Torr, BP=95° C.) to give the title compound (2.99 g, 61% yield) as an oil.

'H NMR (500 MHz, CDCl ₃ ) δ 1.48 (m, 4H), 1.45 (s, 9H), 1.12 (m, 2H), 0.92 (m, 3H), 0.61 (m, 2H).

Intermediate 2B. (1-Propylcyclopropyl)methanol

To a solution of intermediate 2A (250 mg, 1.36 mmol) in Et ₂ O (5 ml) was added LiAlH ₄ (103 mg, 2.71 mmol) in portions at room temperature; the reaction mixture was stirred overnight at room temperature. The mixture was treated successively with water (0.1 ml), 15% aq. NaOH (0.1 ml) and water (0.3 ml), then stirred at room temperature for 1 h, dried (MgSO ₄ ) and concentrated in vacuo. The residue was distilled under reduced pressure to give slightly impure title compound (186 mg) as an oil.

‘H NMR (500 MHz, CDCI3) δ 3.44 (br s, 2H), 1.48-1.36 (m, 4H), 0.93 (t, J=7.0 Hz, 3H), 0.44-0.27 (m, 4H).

Intermediate 2.

To a solution of intermediate 2B (155 mg, 1.36 mmol) in CH ₂ Cl ₂ (10 ml) at room temperature was added pyridine (0.44 ml, 5.43 mmol) and 4-nitrophenyl chloroformate (410 mg, 2. 04 mmol). After stirring for 2 hours at room temperature, the reaction mixture was concentrated in vacuo and the residue was subjected to chromatography (SiO ₂ ; continuous gradient 0-25% EtOAc in hexanes) to give the title intermediate 2 (226 mg, 60% yield) as white solid.

'H NMR (500 MHz, CDCl ₃ ) δ 8.31 (d, J=9.1 Hz, 2H), 7.42 (d, J=9.1 Hz, 2H), 4.15 (s, 2H), 1.45 (m, 4H), 0.96 (t, J=7.0 Hz, 3H), 0.58 (m, 2H), 0.51 (m, 2H).

The following intermediates were prepared using the same synthetic sequence as for intermediate 2, starting with t-butyl cyclopropanecarboxylate or t-butyl cyclobutanecarboxylate, and then subjected to alkylation with the appropriate alkyl iodide or alkyl bromide.

Intermediate 3. (1-Methylcyclopropyl)methyl (4-nitrophenyl)carbonate

1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=9.2 Hz, 2H), 7.40 (d, J=9.2 Hz, 2H), 4.10 (s, 2H), 1.22 (s, 3H), 0.60 ( m, 2H), 0.47 (m, 2H).

Intermediate 4. (1-Ethylcyclopropyl)methyl (4-nitrophenyl)carbonate

1H NMR (400 MHz, CDCI3) δ 8.28 (d, J=9.2 Hz, 2H), 7.39 (d, J=9.2 Hz, 2H), 4.14 (s, 2H), 1.48 (q, J=7.3 Hz, 2H ), 0.98 (t, J=7.4 Hz, 3Н), 0.54 (m, 4H).

Intermediate 5. (1-Ethylcyclobutyl)methyl(4-nitrophenyl)carbonate

1H NMR (500 MHz, CDCI3) δ 8.31 (d, J=9.4 Hz, 2H), 7.42 (d, J=9.4 Hz, 2H), 4.27 (s, 2H), 1.99-1.83 (m, 6H), 1.63 (q, J=7.4 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 6 4-Nitrophenyl((1-propylcyclobutyl)methyl)carbonate

'H NMR (500 MHz, CDCI3) δ 8.31 (d, J=9.4 Hz, 2H), 7.42 (d, J=9.4 Hz, 2H), 4.26 (s, 2H), 1.99-1.85 (m, 6H), 1.56 (m, 2H), 1.32 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

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table 2

Etc. No. Structure and name Analytical and biological data Method 47 9 G I .. \F (lS,3S)-3-((6-(5-((((3fluorocyclobutyl)methoxy)carbonyl)amino)methyl)-1-methyl-1 Η-1,2,3-triazol-4 yl)pyridine -3 -yl)oxy)cyclohexane-1 carboxylic acid (mixture of cis/trans isomers) LCMS, [M + H] ⁺ = 462; Ή NMR (500 MHz, DMSO-de) δ 8.36 (d, 7=2.4 Hz, 1H), 7.98 (d, 7=8.5 Hz, 1H), 7.55 (m, 2H), 5.22 -5.02 (m, 1H) , 4.81-4.76 (m, 1H), 4.73 (m, 2H), 4.06 (s, 3H), 3.94 (m, 2H), 2.68 (m, 1H), 2.44 (m, 1H), 2.30 - 2.05 (m , 4H), 2.03 - 1.93 (m, 1H), 1.89 - 1.73 (m, 3H), 1.72-1.43 (m, 4H); hLPAi IC ₅₀ = 854 hM. Example 5 48 .HE ? G N-N N \F (lS,3S)-3-((6-(5-((((3fluorocyclobutyl)methoxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4yl) -2 - methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid (mixture of cis/trans isomers of fluorocyclobutane) LCMS, [M+H] ⁺ =476; Ή NMR (500 MHz, DMSOde) δ 7.82 (br d, 7=8.5 Hz, 1H), 7.63 (br s, 1H), 7.47 (br d, 7=8.7 Hz, 1H), 5.19-5.00 (m, 1H ), 4.82 -4.70 (m, 3H), 4.04 (s,2H), 3.96 -3.87 (m, 2H), 2.61 (m, 1H), 2.44 (m, 4H), 2.28 - 2.04 (m, 4H), 2.98 (m, 1H), 1.88-1.71 (m, 3H), 1.70-1.42 (m, 4H); hLPAi IC ₅₀ = 48 hM. Example 1 49 /A Ν-Ν Η /\ (1 S,3 S)-3-((6-(5-(((((1-fluorocyclopropyl)methoxy)carbonyl)amino)methyl) -1 methyl- 1H-1,2,3-triazole-4- yl)-2methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =462; Ή NMR (500 MHz, DMSOde) δ 7.82 (br d, 7=8.9 Hz, 1H), 7.78 (br s, 1H), 7.48 (br d, 7=8.5 Hz, 1H), 4.74 (m, 3H), 4.32-4.19 (m, 2H), 4.05 (s, 3H), 2.62 (m, 1H), 2.44 (s, 3H), 2.02-1.92 (m, 1H), 1.90 -1.72 (m, 4H), 1.68 - 1.44 (m, 4H), 1.07 - 0.96 (m, 2H), 0.80 - 0.72 (m, 2H); hLPAj IC ₅₀ = 602 hM. Example 1 50 W \ H -, / OH 9 f ml^ N-N^ N △ (1 S,3 S)-3-((6-(1-methyl-5-(((((1 propylcyclopropyl)methoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl) pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =472; Ή NMR (500 MHz, DMSOde) δ 8.34 (d, 7=2.4 Hz, 1H), 7.98 (d, 7=8.8 Hz, 1H), 7.52 (dd, 7=8.7, 2.7 Hz, 1H), 7.33 (br s, 1H), 4.77 (m, 1H), 4.72 (m, 2H), 4.06 (s, 3H), 3.79 (s, 2H), 2.72 - 2.64 (m, 1H), 2.02 - 1.93 (m, 1H) , 1.91 - 1.71 (m, 4H), 1.67 (m, 2H), 1.60-1.49 (m, 2H), 1.32-1.17 (m, 4H), 0.79 (t, 7=7.1Hz, ZN), 0.36 (br s, 2H), 0.27 (brs, 2H); hLPAj IC ₅₀ = 28 hM. Example 5

- 70 042829

51 „AJ ,, ΛΗ 9 f S V, Ν-Ν^ Η ΖΛ (1 S,3 S)-3 -((6-(5 -(((((1 -ethylcyclopropyl)methoxy)carbonyl)amino)methyl)-1 methyl- 1H-1,2,3-triazole-4- yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 258; Ή NMR (500 MHz, DMSOd ₆ ) δ 8.35 (d, 7=2.4 Hz, 1H), 7.97 (d, 7=8.9 Hz, 1H), 7.53 (dd, 7=8.7, 2.6 Hz, 1H), 7.48 ( br s, 1H), 4.77 (m, 1H), 4.74 - 4.70 (m, 2H), 4.06 (s, 3H), 3.82 - 3.53 (m, 2H), 2.692.63 (m, 1H), 2.00 - 1.94 (m, 1H), 1.91-1.73 (m, 4H), 1.71 - 1.59(m, 2H), 1.58 - 1.46 (m, 2H), 1.30 - 1.22 (m, 2H), 0.86 - 0.77 (m, 3H) , 0.36 (br s, 2H), 0.28 (br s, 2H); hLPAi IC ₅₀ = 62 nM. Example 5 52 9^ 1f :P, N-N^ Η /\ (1 S,3 S)-3-((6-(1-methyl-5-(((((1 methylcyclopropyl)methoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl) pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =444; Ή NMR (500 MHz, DMSOd ₆ ) δ 8.37 (d, 7=2.1 Hz, 1H), 7.99 (d, 7=8.9 Hz, 1H), 7.54 (dd, 7=8.9, 2.7 Hz, 1H), 7.52 ( br s, 1H), 4.78 (m, 1H), 4.76–4.72 (m, 2H), 4.07 (s, 3H), 3.79–3.60 (m, 2H), 2.71–2.63 (m, 1H), 2.04–1.91 ( m, 1H), 1.89 - 1.74 (m, 4H), 1.71 - 1.63 (m, 2H), 1.59 - 1.52 (m, 2H), 1.03 (brs, 3H), 0.41 (br s, 2H), 0.28 (br s, 2H); hLPAj IC ₅₀ = 81 nM. Example 5 53 .О ⁿ 9 if X «° NN Η (1 S,3 S)-3 -((6-(5 -((((3-methoxypropoxy)carbonyl)amino)methyl)-1-methyl 1 Η-1, 2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ =462; Ή NMR (500 MHz, DMSO-d ₆ ) δ 7.83 (brd, 7=8.5 Hz, 1H), 7.54 (br s, 1H), 7.48 (d, 7=8.9 Hz, 1H), 4.82-4.71 (m, 3H), 4.05 (s, 3H), 4.01 -3.95 (m, 2H), 3.95 -3.85 (m, 2H), 3.18 (brs, 3H), 2.69 -2.58 (m, 1H), 2.44 (s, 3H) , 2.05 - 1.97 (m, 1H), 1.91 - 1.45 (m, 9H); hLPAj IC ₅₀ = 342 nM. Example 1

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54 A___А„ / ^0Н 9 Г V ° Ν-Ν Η / H (1 S,3 S)-3 - ((2-methyl-6-( 1 -methyl-5 - (((((1 propylcyclobutyl) methoxy) carbonyl )amino) methyl) -1 Η-1,2,3 -triazo l4-yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 500; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.83 (br d, 7=8.5 Hz, 1H), 7.63 (br s, 1H), 7.48 (d, 7=8.9 Hz, 1H), 4.82 - 4.67 (m, 3H ), 4.04 (s, 3H), 3.94–3.82 (m, 2H), 2.67–2.57 (m, 1H), 2.44 (s, 3H), 2.05–1.97 (m, 1H), 1.92–1.42 (m, 14H ), 1.40 - 1.28 (m, 2H), 1.231.07 (m, 2H), 0.87 - 0.75 (m, 3H); hLPA, IC ₅₀ = 58 nM. Example 1 55 V „° Ν-Ν Η (IS,38)-3-((6-(5-((((3- fluoropropoxy)carbonyl)amino)methyl) -1 methyl-1H-1,2,3-triazol-4-yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =450; Ή NMR (500 MHz, DMSOde) δ 7.82 (d, 7=8.5 Hz, 1H), 7.58 (brs, 1H), 7.47 (d, 7=8.5 Hz, 1H), 4.81 -4.68 (m, 3H), 4.54 -4.36 (m, 2H), 4.04 (s, 4H), 2.63 - 2.56 (m, 1H), 2.43 (s, 3H), 2.01 - 1.89 (m, 2H), 1.86 - 1.74 (m, 4H), 1.641 .43(m, 4H); hLPA ₁ IC ₅₀ = 411 nM. Example 1 56 YvJv/OH 9 С ΑΧ// Ν-Ν^ Η (18.38)-3-((6-(5-((((2-ethoxyethoxy)carbonyl)amino)methyl)-1-methyl- 1H-1,2,3triazol-4-yl)-2-methyl - pyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ =462; Ή NMR (500 MHz, DMSOde) δ 7.82 (d, 7=8.9 Hz, 1H), 7.61 (br s, 1H), 7.47 (d, 7=8.5 Hz, 1H), 4.77 (m, 1H), 4.74 ( br d, 7=5.5 Hz, 2H), 4.083.99 (m, 5H), 3.52 - 3.33 (m, 2H), 2.66 - 2.57 (m, 1H), 2.44 (s, 3H), 2.05 - 1.97 (m , 1H), 1.94-1.71 (m, 4H), 1.681.39 (m, 4H), 1.04 (t, 7=7.0 Hz, ZN); hLPA! IC ₅₀ = 885 nM. Example 1

- 72 042829

57 /Ar γ ” Ν-Ν^ H (1 S,3 S)-3 -((6-(5 -(((((1 -ethylcyclobutyl)methoxy)carbonyl)amino)methyl)-1 methyl- 1H-1,2,3-triazole-4- yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =486; Ή NMR (500 MHz, DMSOde) δ 7.82 (d, 7=8.5 Hz, 1H), 7.62 (br s, 1H), 7.47 (d, 7=8.5 Hz, 1H), 4.80 - 4.70 (m, 3H), 4.04 (s, 3H), 3.93 - 3.48 (m, 2H), 2.66 - 2.57 (m, 1H), 2.43 (s, 3H), 2.05 - 1.95 (m, 1H), 1.92 - 1.33 (m, 15H), 0.770.66 (m, 3H); hLPAi IC ₅₀ = 68 nM. Example 1 58 „D___D/ON N-N^ N △ (1 S,3 S)-3 -((6-(5 -(((((1 -ethylcyclopropyl)methoxy)carbonyl)amino)methyl)-1 methyl- 1H-1,2,3-triazole-4- yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =472; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.82 (br d, 7=8.5 Hz, 1H), 7.59 (br s, 1H), 7.48 (br d, 7=8.5 Hz, 1H), 4.79 (m, 1H) , 4.76 - 4.72 (m, 2H), 4.05 (s, 3H), 3.86 -3.50 (m, 2H), 3.30-3.10 (m, 1H), 2.702.59 (m, 1H), 2.45 (br s, 3H ), 1.97 - 1.75 (m, 5H), 1.691.55 (m, 3H), 1.34-1.21 (m, 2H), 0.85 - 0.79 (m, 3H), 0.41 -0.34 (m, 2H), 0.31-0.26 (m, 2H); hLPAj IC ₅₀ = 38 nM. Example 1 59 A \ D „ / OH 9 - f g ° Ν-Ν\ Η /\ (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -(((((1 methylcyclopropyl)methoxy)carbonyl)amino)methyl)-1 Η-1,2,3 -triazo l4-yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =458; Ή NMR (500 MHz, DMSO-d ₆ ) δ 7.83 -7.78 (m, 1H), 7.60 (br s, 1H), 7.47 (br d, 7=7.6 Hz, 1H), 4.78 (m, 1H), 4.72 (br s, 2H), 4.04 (s, 3H), 3.77–3.55 (m, 2H), 3.31–3.13 (m, 1H), 2.73–2.59 (m, 1H), 2.46 (br s, 3H), 1.93 - 1.50 (m, 8H), 1.00 (m, 3H), 0.42 - 0.35 (m, 2H), 0.31-0.23 (m, 2H); hLPAi IC ₅₀ = 48 nM. Example 1

- 73 042829

60 s, Ν-Ν\ Η (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -(((((1 propylcyclopropyl)methoxy)carbonyl)amino)methyl)-1 Η-1,2,3 -triazo l4-yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =486; Ή NMR (500 MHz, DMSO-de) 5 7.82 (br d, 7=7.7 Hz, 1H), 7.61 (br s, 1H), 7.48 (br d, 7=8.0 Hz, 1H), 4.79 (m, 1H ), 4.73 (m, 2H), 4.04 (s, 3H), 3.82 -3.71 (m, 2H), 2.69 - 2.57 (m, 1H), 2.45 (br s, 3H), 2.09-1.41 (m, 8H) , 1.33 - 1.14 (m, 4H), 0.78 (m, 3H), 0.36 (br s, 2H), 0.27 (br s, 2H); hLPAi IC ₅₀ = 12 nM. Example 1 61 A / he νΆ y -9 "Λ-χ, -ν NN ^ H ⁰ (lS,3S) -3- ((5- (5- ((((benzyloxy) carbonyl) amino) methyl) -1 methyl- 1H -1,2,3-triazol-4-yl)-3 methylpyrazin-2-yl)oxy)cyclohexane-1 carboxylic acid [M + H] ⁺ = 481; Ή NMR (500 MHz, CDC1 ₃ ) d 8.81 (s, 1H), 7.45-7.31 (m, 5H), 5.54 (br. s., 1H), 5.11 (s, 2H), 4.66 (s, 2H), 4.25 (s, 3H), 2.85 (tt, J=11.3, 3.5Hz, 1H), 2.54 (s, 3H), 2.31 (d, 1=14.0Hz, 1H), 2.14-1.96 (m, 2H), 1.931 .55 (m, 5H) Rapid in vivo histamine assay in CD-I mice: -63% histamine at 1 mg/kg of the compound of Example 61. Example 1 62 Αζ o ST T O Ν-Ν Η ° \ (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -((((rtolyloxy)carbonyl)amino)methyl)-1H1,2,3-triazol-4-yl) pyride in-3 yl)oxy)cyclohexane-1-carboxylic acid [M + H] ⁺ = 480.2; Ή NMR (400 MHz, CDC1 ₃ ) 5 8.07 (d, 7=8.6 Hz, 1H), 7.71 (br d, 7=8.8 Hz, 1H), 7.12 (d, 7=8.1 Hz, 2H), 6.94 (d , 7=8.6 Hz, 2H), 4.79 (br s, 1H), 4.69 (s, 2H), 4.22 (s, 3H), 2.92-2.83 (br, 1H), 2.63 (s, 3H), 2.32 (s , ZN), 2.15 - 1.59 (w, 9H); hLPAi 1C ₅₀ = 148 nM. Example 1 63 /θ¥ ^0Η /k/ ⁰ Cl Ν-Ν^ H ⁰ (1 S,3 S)-3 -((6-(5 -((((4-methoxy- [M + H] ⁺ = 496.2; Ή NMR (400 MHz, CDC1 ₃ ) 5 8.06 (d, 7=8.6 Hz, 1H), 7.61 (br d, 7=9.2 Hz, 1H), 6.98 (d, 7=9.2 Hz, 2H), 6.89-6.81 (br, 2H), 4.79 (br s, 1H), 4.69 (s, 2H), 4.22 (s, 3H), 3.78 (s, 3H), 2.62 (s, 3H), 2.12-2.04 (br, 2H) , 2.00 - 1.58 (br, 8H); hLPAi Example 1 phenoxy)carbonyl)amino)methyl)-1 methyl-1 Η-1,2,3-triazo l-4-yl) -2 methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid 1C ₅₀ = 792 nM.

Example 64 (1S,3S)-3-((6-(5-((tert-Butoxycarbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid

64A. Methyl (1S,3S)-3-((6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1 -carboxylate

To a stirred solution of methyl (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)-2-methylpyridin-3-yl)oxy) cyclohexane-1-carboxylate (synthesized analogously to the corresponding isopropyl ester in example 1E; 3.28 g, 9.10 mmol) in CH ₂ Cl ₂ (45.5 ml) adding

- 74 042829 NaHCO ₃ (3.82 g, 45.5 mmol) and Dess-Martin periodinan (4.63 g, 10.9 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The white solid was filtered off through Celite® and washed with EtOAc. The combined filtrates were washed with saturated aqueous NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was chromatographed (120 g Redisep® SiO ₂ column; isocratic elution with 60% EtOAc in hexane) to give the title compound as a clear colorless oil (3.10 g, 95%).

LC-MS [M+H]+ = 359.1.

¹ H NMR (500 MHz, CDCl3) δ 10.96 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 4.77-4.72 (m, 1H), 4.36 (s, 3H), 3.70 (s, 3H), 2.87-2.80 (m, 1H), 2.51 (s, 3H), 2.20-2.08 (m, 1H), 2.02-1.91 (m, 3H), 1.80- 1.59(m, 4H).

64b. 4-(5-(((1S,3S)-3-(Methoxycarbonyl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H1,2,3-triazole-5-carboxylic acid

To a mixture of the compound of Example 64A (260 mg, 0.725 mmol), NaH ₂ PO ₄ (435 mg, 3.63 mmol), 2-methyl 2-butene (0.617 ml of a 2.0 M solution in THF; 5.80 mmol), water (0.2 ml) and t-BuOH (2 ml) NaClO ₂ (131 mg, 1.45 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h, then poured into brine and extracted with EtOAc (3 times). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound. The crude acid was used in the next reaction without further purification.

1H NMR (500 MHz, CDCl ₃ ) δ 8.52-8.19 (m, 1H), 7.67-7.40 (m, 1H), 4.85-4.75 (m, 1H), 4.52-4.40 (m, 3H), 3.78-3.63 ( m, 3H), 2.90-2.77 (m, 1H), 2.67-2.53 (m, 3H), 1.99-1.83 (m, 3H), 1.80-1.62 (m, 5H).

64C. Methyl (1 S,3 S)-3 -((6-(5-((tert-butoxycarbonyl)amino)-1 -methyl- 1H-1,2,3-triazol-4-yl)-2methylpyridin-3 - yl)oxy)cyclohexane-1-carboxylate

A mixture of the compound of Example 64B (60 mg, 0.160 mmol), diphenylphosphoryl azide (63 μl, 0.288 mmol), 2-methylpropan-2-ol (36 mg, 0.240 mmol), TEA (89 μl, 0.641 mmol) in toluene (1 ml ) was stirred at 80°C for 1 h, then cooled to room temperature and concentrated in vacuo. LC/MS analysis indicated the formation of the desired product. The crude product was chromatographed (12 g SiO2; continuous gradient from 0 to 80% EtOAc in hexanes over 30 min and 80% EtOAc/hexanes over 20 min) to give the title compound (60 mg, 0.135 mmol, 84% yield ).

1H NMR (400 MHz, CDCl3) δ 8.00-7.81 (m, 1H), 7.28-7.15 (m, 1H), 4.84-4.62 (m, 1H), 4.14-4.06 (m, 3H), 3.76-3.67 (m , 3Н), 2.92-2.77 (m, 1H), 2.57-2.49 (m, 3Н), 2.25-2.09 (m, 1H), 2.05-1.60 (m, 8H), 1.58-1.48 (m, 9H)

Example 64.

To a stirred solution of the compound of Example 64C (30 mg, 0.067 mmol) in THF (1.5 ml), MeOH (0.100 ml) and water (0.15 ml) at room temperature was added 2.0 M aqueous LiOH (0.101 ml, 0.202 mmol). The mixture was stirred at 50°C for 1 h, then cooled to room temperature and acidified to pH 2.3 by dropwise addition of 1M aq. HCl. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC ((Sunfire C18, 150x19 mm; 5 μm; mobile phase A: 10 mM NH ₄ OAc in water (pH: 4.5); mobile phase B: MeCN, flow rate: 15 ml /min; time (min)/%B: 0/20, 25/60; retention time: 15.19 min)) to give the title compound (15 mg, 0.031 mmol, 46.5% yield).

LCMS [M+H]+= 460.2.

1H NMR (400 MHz, CDCl3) δ 8.03-7.85 (m, 1H), 7.26-7.22 (m, 1H), 4.77-4.66 (m, 1H), 4.15-4.05 (m, 3H), 2.92-2.75 (m , 1H), 2.56-2.43 (m, 3H), 2.23-2.08 (m, 1H), 2.05-1.85 (m, 3H), 1.82-1.61 (m, 4H), 1.60-1.48 (m, 9H).

LCMS [M+H] ⁺ = 446.2. hLPA1 IC ₅₀ = 54 nM.

In table. 3 shows compounds according to additional examples. Some of these compounds are

- 75 042829 examples (103-107) were synthesized using a triazole-ethanol intermediate (shown below). Specifically, Intermediate 7, an alcohol, was converted to the compounds of the following examples using the same method and procedure as shown in Scheme 1 and illustrated by the 5-step conversion of Intermediate 1E to the compound of Example 1.

Intermediate 7 Methyl (1S,3S)-3-((6-(5-(2-hydroxyethyl)-1-methyl-1H-1,2,3-triazol-4yl)-2-methylpyridin-3-yl )oxy)cyclohexane-1-carboxylate

Ar °'

N—

7A. Methyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-vinyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane -1 -carboxylate

To a suspension of Ph ₃ PCH ₃ Br (3.77 g, 10.6 mmol) in THF (70 ml) at 0°C was added KOtBu (0.947 g, 8.44 mmol) and the reaction mixture was stirred at 0°C for 30 min. To the reaction mixture was added a solution of the compound of example 241A (2.52 g, 7.03 mmol) in THF (10 ml), which was stirred at 0°C for 30 min, then allowed to warm to room temperature. The reaction mixture was stirred for 1 h at room temperature, then quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was extracted with EtOAc (2x25 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was chromatographed (220 g Redisep® SiO ₂ column; continuous gradient from 0-60% EtOAc in hexane) to give the title compound as a white gum (2.2 g, 88%).

LC-MS [M+H]+ = 357.0.

¹ H NMR (500 MHz, CDCl3) δ 7.91 (d, J=8.5 Hz, 1H), 7.42 (dd, J=18.3, 12.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 5.93- 5.88 (m, 1H), 5.70-5.66 (m, 1H), 4.71 (br s, 1H), 4.15 (s, 3H), 3.70 (s, 3H), 2.84 (tt, J=10.5, 3.9 Hz, 1H ), 2.53 (s, 3H), 2.16 (br d, J=13.8 Hz, 1H), 2.02-1.87 (m, 3H), 1.87-1.71 (m, 1H), 1.71-1.54 (m, 3H).

Intermediate 7.

To a solution of intermediate 7A (1.45 g, 4.07 mmol) in THF (13.6 ml) at 0°C was added 9-BBN (17.9 ml of a 0.5 M solution in THF; 8.95 mmol). The ice bath was removed and the reaction mixture was heated at 65°C for 4 h, then cooled to 0°C. A solution of sodium perborate tetrahydrate (2.50 g, 16.3 mmol) in water (10 ml) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 18 hours; then water was added. The aqueous layer was extracted with EtOAc (2x20 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was chromatographed (120 g Redisep® SiO2 column; continuous gradient from 0 to 100% EtOAc in hexane) to give the title compound as a colorless oil (0.37 g, 24%).

LC-MS [M+H] ⁺ = 375.1.

1Н NMR (400 MHz, CDCl3) δ 7.92 (d, J=8.6 Hz, 1H), 7.30-7.25 (m, 1H), 6.71-6.42 (m, 1H), 4.74-4.68 (m, 1H), 4.06- 3.98 (m, 5H), 3.70 (s, 3H), 3.26 (td, J=5.6, 1.4 Hz, 2H), 2.83 (tt, J=10.3, 3.9 Hz, 1H), 2.51 (s, 3H), 2.14 (dt, J=13.9, 4.3 Hz, 1H), 2.02-1.87 (m, 3H), 1.82-1.56 (m, 4H).

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Table 3

Etc. No. Structure and name Analytical and biological data Method 65 οΌγ ⁰ U ^Ν Λ o (1 S,3 S) -3 - ((6- (5 - (((3,3 -dimethylbutoxy) carbonyl) amino) -1 -methyl- 1H1,2,3-triazole-4 -yl)-2-methyl-pyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.2; Ή NMR (500 MHz, CDCI3) δ 8.24 - 8.09 (m, 1H), 7.97-7.82 (m, 1H), 4.93-4.80 (m, 1H), 4.594.38 (m, 7H), 4.29-4.14 (m , 3H), 4.12-3.95 (m, 3H), 3.00-2.85 (m, 1H), 2.84-2.63 (m, 3H), 2.28 2.13 (m, 1H), 2.01-1.51 (m, 9H), 1.11- 0.75 (m, 9H); hLPAi IC ₅₀ = 75 nM. Example 64 and Diagram 7 66 Λ 0G ^he Luo. ^Ν Λ ό Q (18.38) -3- ((6- (5- (((cyclopentyloxy) carbonyl) amino) -1 -methyl-1 Η-1,2,3 triazol-4-yl) -2- methylpyridin-3-yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 444.0; SNMR (500 MHz, DMSO-d ₆ ) δ 7.68 - 7.42 (m, 2H), 5.14-4.94 (m, 1H), 4.86-4.67 (m, 3H), 3.69-3.29 (m, 3H), 3.243.11 (m, 1H), 2.37-1.28 (m, 16H); hLPAi IC ₅₀ = 68 nM. Example 64 and scheme 7 67 y “ ^Ν ' y ° .. y ^Ν -\ o (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 (((neopentyloxy) carbonyl) amino) -1H1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.2; SNMR (400 MHz, CDC1 ₃ ) δ 8.23 - 8.06 (m, 1H), 8.02-7.88 (m, 1H), 4.96-4.78 (m, 1H), 4.134.03 (m, 3H), 3.93-3.79 (m , 2H), 2.98 - 2.86 (m, 1H), 2.83 -2.68 (m, 3H), 2.28-2.11 (m, 1H), 2.O21.62 (m, 7H), 1.10-0.90 (m, 9H) ; hLPAi IC ₅₀ = 72 hM. Example 64 and scheme 7

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68 Ή ^N \ 0 (1 S,3 S)-3 -((2-methyl-6-( 1-methyl-5 ((propoxycarbonyl)amino)- 1H-1,2,3triazol-4-yl)pyridine-3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 418.2; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.23 - 8.08 (m, 1H), 8.00-7.85 (m, 1H), 5.48-5.04 (m, 1H), 4.894.79 (m, 1H), 4.21-4.00 ( m, 5H), 2.99 - 2.86 (m, 1H), 2.82-2.70 (m, 3H), 2.27-2.14 (m, 1H), 2.O21.59 (m, 9H), 1.04-0.92 (m, 3H ); hLPAi IC ₅₀ = 89 hM. Example 64 and scheme 7 69 X ° ^Ν Λ o m (1 S,3 S)-3 -((6-(5 -(((1 -cyclopropylethoxy)carbonyl)amino)-1 -methyl- 1H-1,2,3triazo l-4 - yl) -2-methyl-pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers at CH) LCMS, [M + H] ⁺ = 444.0; NMR (500 MHz, DMSO-d ₆ ) δ 7.54 - 7.37 (m, 1H), 7.32-7.13 (m, 1H), 4.62-4.44 (m, 1H), 4.05 - 3.93 (m, 1H), 3.64 (s , 3H), 2.28-2.11 (m, 6H), 1.85 - 1.54 (m, 4H), 1.49-1.17 (m, 4H), 1.060.87 (m, 4H), 0.26 to -0.04 (m, 4H); hLPAi IC ₅₀ = 85 nM. Example 64 and scheme 7 70 X “ ^N ” \ about g (lS,3S) -3- ((6- (5- ((isopropoxycarbonyl) amino) -1-methyl1H-1,2,3-triazol-4-yl) -2-methylpyridin- 3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 418.2; 'HNMR (400 MHz, CDC1 ₃ ) δ 8.27 - 8.09 (m, 1H), 8.01-7.88 (m, 1H), 6.66-6.12 (m, 1H), 5.054.79 (m, 2H), 4.15-3.98 ( m, 3H), 2.99 - 2.86 (m, 1H), 2.82-2.70 (m, 3H), 2.29-2.15 (m, 1H), 2.O61.60 (m, 8H), 1.38-1.16 (m, 6H ); hLPAi IC ₅₀ = 129 nM. Example 64 and scheme 7 71 G / m ^Ν Α o \ (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 - LCMS, [M + H] ⁺ = 446.1; 'HNMR (400 MHz, CDC1 ₃ ) δ 8.20 - 8.01 (m, 1H), 7.80-7.65 (m, 1H), 4.93 - 4.73 (m, 1H), 4.25 4.14 (m, 2H), 4.11-3.97 (m , 3H), 2.73-2.64 (m, 4H), 2.25-1.61 (m, 11H), 1.45-1.26 (m, 4H), 1.000.84 (m, 3H); Example 64 and scheme 7

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(((pentyloxy)carbonyl)amino)- 1H-1,2,3triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid hLPAi 1C ₅₀ =6nM. 72 oX'T ° ά ° ⁿ ΑνΟ o (1S, 3 S) -3 - ((2-methyl-6-( 1 -methyl-5 - ((((R) -1 - phenylethoxy) carbonyl) amino) - 1H -1,2,3tr iazo l-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 480.1; Ή NMR (400 MHz, CDCI3) δ 8.13 - 8.02 (br, 1H), 7.83 - 7.72 (br, 1H), 7.45-7.31 (br, 5H), 5.925.75 (br, 1H), 4.87-4.76 (br , 1H), 4.06-3.92 (br, W), 2.97-2.87 (m, 2H), 2.76-2.72 (br, 1H), 2.702.61 (br, W), 2.21-2.11 (w, 1H), 2.05 - 1.73 (br, 6H), 1.70-1.56 (br, 4H); hLPAi 1C ₅₀ = 26 nM. Example 64 and scheme 7 73 Jr A ° ^Ν Λ o (1 S,3 S) -3 - ((6- (5 - (((2-cyclopropylethoxy) carbonyl) amino) -1 -methyl- 1H-1,2,3 triazo l-4 - yl) -2-methyl-pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 444.1; Ή NMR (400 MHz, CD ₃ CN) δ 7.97 - 7.69 (m, 2H), 4.95 - 4.76 (m, 1H), 4.29-4.01 (br, 2H), 3.923.75 (br, 3H), 2.83-2.49 (br, 4H), 2.10-1.91 (br, 2H), 1.83-1.33 (br, 8H), 0.84-0.56 (br, 1H), 0.450.17 (br, 2H), 0.06-0.08 (m, 2H) ; hLPAi 1C ₅₀ = P nM. Example 64 and scheme 7 74 A ” ^Ν Λ o (1 S,3 S) -3 - ((6- (5 - (((cyclopropylmethoxy) carbonyl) amino) -1 -methyl- 1H1,2,3-triazol-4-yl) -2 -methyl-pyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 430.2; Ή NMR (400 MHz, CD ₃ CN) δ 8.08 - 7.85 (t, 2H), 5.08 -4.76 (t, 1H), 4.14-3.84 (t, 5H), 2.872.75 (t, 1H), 2.74 -2.68 (t, GL), 2.67 - 2.63 (t, 1Н), 2.19 - 2.07 (t, 1Н), 1.93 - 1.86 (t, GL), 1.84 1.56 (t, 4Н), 1.29-1.03 (t, 1Н), 0.71-0.52 (t, 2H), 0.45-0.13 (t, 2H); hLPAi 1C ₅₀ = 14 nM. Example 64 and scheme 7

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75 &" Ν-Ν D \ o (18.38)-3-((6-(5-(((cyclobutylmethoxy)carbonyl)amino)-1-methyl-1H1,2,3-triazol-4-yl)-2-methyl-pyridin-3yl )oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 444.1; Ή NMR (500 MHz, DMSO-de) δ 7.81 - 7.65 (m, 1H), 7.55 - 7.39 (m, 1H), 4.80-4.68 (m, 2H), 4.01 (br d, 7=4.7 Hz, ZN) , 3.88 (s, 4H), 2.71-2.61 (m, 1H), 2.58-2.54 (m, 5H), 2.45-2.29 (m, 4H), 2.10-1.40 (m, 7H); hLPAi IC ₅₀ = 22 hM. Example 64 and scheme 7 76 0G ^N - \ O (1 S,3 S) -3 - ((6- (5 - (((cyclohexylmethoxy) carbonyl) amino) -1 -methyl- 1H1,2,3-triazol-4-yl) -2 -methyl-pyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 472.2; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.21 - 8.10 (m, 1H), 7.95 - 7.85 (m, 1H), 7.18-6.61 (m, 1H), 4.914.76 (m, 1H), 4.13-4.04 ( m, 3H), 4.01-3.91 (m, 2H), 3.00-2.84 (m, 1H), 2.81-2.70 (m, 3H), 2.292.14 (m, 1H), 2.04-1.40 (m, 14H), 1.40-1.08 (m, 3H), 1.05-0.86 (m, 2H); hLPAi IC ₅₀ = 19 hM. Example 64 and scheme 7 77 U ° cUU / ^Ν Λ about y (1 S,3 S) -3 - ((6- (5 - (((isopentyloxy) carbonyl) amino) -1 -methyl-1 Η-1,2,3 triazole-4 -yl)-2-methylpyridin-3-yl) hydroxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.1; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.07 - 7.94 (m, 1H), 7.61 -7.43 (m, 1H), 4.88 -4.70 (m, 1H), 4.294.17 (m, 2H), 4.13-4.03 ( m, 3H), 2.99-2.87 (m, 1H), 2.66-2.59 (m, 3H), 2.18-2.06 (m, 4H), 1.801.68 (m, 6H), 1.63-1.55 (m, 2H), 1.02-0.91 (m, 6H); hLPAi IC ₅₀ = 20 hM. Example 64 and scheme 7 78 έτ ^he Luo / ^Ν -\ O (1 S,3 S) -3 - ((6-(5 - ((isobutoxy- LCMS, [M + H] ⁺ = 432.1; 'HNMR (500 MHz, CDC1 ₃ ) δ 8.18 - 8.06 (m, 1H), 7.81-7.69 (m, 1H), 4.94-4.74 (m, 1H), 4.184.02 (m, 3H), 3.99-3.88 ( m, 2H), 2.98-2.85 (m, 1H), 2.78-2.64 (m, 3H), 2.23-1.62 (m, 10H), 0.98 (d, 7=6.6 Hz, 6H); Example 64 and scheme 7

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carbonyl)amino)-1-methyl-1 Η-1,2,3 triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid hLPAi 1C ₅₀ = 29 nM. 79 γθγ ⁰ δ (lS,3S)-3 -((6-(5(((cyclopentylmethoxy)carbonyl)amino)1 -methyl-1 Η-1,2,3 -triazol-4 -yl) -2methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 458.2; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.68-8.29 (m, 2H), 8.17 (d, 7=8.8 Hz, 1H), 7.97-7.88 (m, 1H), 4.92-4.77 (m, 1H), 4.134 .01 (t, 5H), 2.97-2.86 (t, 1H), 2.80-2.75 (t, GL), 2.33-2.15 (t, 2H), 2.00-1.53 (t, 13H), 1.35-1.19 (t, 2H); hLPAi 1C ₅₀ = 32 nM. Example 64 and scheme 7 80 A ¹ / G ” TrD (1 S,3 S) -3 - ((6- (5 - (((benzyloxy) carbonyl) amino) -1 -methyl-1 Η-1,2,3 triazol-4-yl )-2-methylpyridin-3-yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 466.0; Ή NMR (500 MHz, DMSO-de) δ 7.49 -7.14 (t, 7H), 5.27-4.98 (t, 2H), 4.83 - 4.66 (t, 1H), 4.01-3.76 (t, 3H), 2.602.54 (t, 4H), 2.37 - 2.20 (t, GL), 2.13 - 1.99 (t, 1H), 1.95 - 1.73 (t, 2H), 1.70-1.41 (t, 4H). hLPAi 1C ₅₀ = 37 nM. Example 64 and scheme 7 81 ά ° ^N \ δ ⁷ (18.38)-3-((6-(5-(((cyclobutylmethoxy)carbonyl)amino)-1-methyl-1H1,2,3-triazol-4-yl)pyridine- 3 -yl) hydroxy) cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 430.4; Ή NMR (500 MHz, DMSO-de) δ 8.29 (br d, 7=2.4 Hz, 1H), 7.88 (d, 7=8.5 Hz, 1H), 7.52 (dd, 7=8.9, 2.7 Hz, 1H), 4.77 (br s, 1H), 4.01 (brs, 1H), 3.87 (s, 3H), 2.65 (br s, 1H), 2.57 -2.55 (m, 2H), 2.24 1.31 (m, 14H); hLPAi IC ₅₀ = 56 nM. Example 64 and scheme 7

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82 δ°Gt ^N \0(1S,3S)-3-((6-(5-((((R)-1-cyclopropyl ethoxy)carbonyl)amino)-1-methyl-1H-1,2, 3triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 430.3; Ή NMR (500 MHz, DMSO-de) δ 9.84 - 9.04 (m, 1H), 8.29 (d, 7=2.4 Hz, 1H), 7.87 (d, 7=8.9 Hz, 1H), 7.52 (dd, 7= 8.7, 2.6 Hz, 1H), 4.76 (br s, 1H), 4.19 (brs, 1H), 3.88 (s, 3H), 3.61–3.47 (m, 1H), 2.01–1.42 (m, 9H), 1.390. 82 (m, 3H), 0.61-0.16 (m, 4H); hLPAi IC ₅₀ = 79 nM. Example 64 and scheme 7 83 A° δ ° A (1 S,3 S)-3 -((6-(5 -(((cyclopropylmethoxy)carbonyl)amino)-1 -methyl- 1H1,2,3-triazol-4-yl)pyridin-3-yl) hydroxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 416.2; Ή NMR (500 MHz, DMSO-de) δ 8.08 (br s, 1H), 7.67 (br d, 7=8.9 Hz, 1H), 7.31 (dd, 7=8.7, 2.3 Hz, 1H), 4.55 (br s , 1H), 3.66 (s, 3H), 2.44 (br s, 1H), 2.34 (s, 2H), 1.73 (br d, 7=13.4 Hz, 1H), 1.661.54 (m, 3H), 1.44 ( brd, 7=8.5 Hz, 2H), 1.37-1.25 (m, 2H), 1.01-0.63 (m, 1H), 0.42 - -0.20 (m, 4H); hLPAi IC ₅₀ = 178 nM. Example 64 and scheme 7 84 δ “ Αύ_ ^Ν Λ 0 Μ (1 S,3 S)-3 -((6-(5 -(((2-cyclopropylethoxy)carbonyl)amino)-1 -methyl- 1H-1,2,3triazole-4- yl) pyridin-3 -yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 430.1; Ή NMR (500 MHz, DMSO-de) δ 8.26 (d, 7=2.4 Hz, 1H), 7.85 (d, 7=8.9 Hz, 1H), 7.50 (dd, 7=8.5, 2.4 Hz, 1H), 4.83 -4.67 (m, lH), 4.15-3.99(m, 1H), 3.85 (s, 3H), 2.67-2.56 (m, 1H), 2.55 -2.53 (m, 2H), 1.95 - 1.80 (m, 2H) , 1.79-1.23 (m, 8H), 0.48 0.20 (m, 4H); hLPAi IC ₅₀ = 38 nM. Example 64 and scheme 7

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85 o^f ⁰ δ ° ^Ν Λ 0 )- (1 S,3 S)-3 -((6-(5 -(((isopentyloxy) carbonyl)amino) -1 -methyl-1 Η-1,2,3 triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 432.3; Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (br s, 1H), 7.87 (br d, 7=8.9 Hz, 1H), 7.50 (br d, 7=6.7 Hz, 1H), 4.73 (brs, 1H), 4.193.42 (m, 3H), 2.64 (br s, 1H), 2.55 (s, 1H), 1.89 (br d, 7=18.0 Hz, 1H), 1.75 (br s, 1H), 1.69 - 1.50 (m, 6H), 1.45 - 1.34 (m, 2H), 1.27 (br s, 3H), 0.82 (br d, 7=6.7 Hz, 6H); hLPAi IC ₅₀ = 115 nM. Example 64 and scheme 7 86 δ” Ν-Ν D \ o (1 S,3 S)-3 -((6-(5 -(((cyclohexylmethoxy)carbonyl)amino)-1 -methyl- 1H1,2,3-triazol-4-yl)pyridin-3-yl) hydroxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.2; Ή NMR (500 MHz, DMSO-de) δ 8.24 (d, 7=2.4 Hz, 1H), 7.86 (d, 7=8.5 Hz, 1H), 7.50 (dd, 7=8.7, 2.6 Hz, 1H), 4.73 (br s, 1H), 4.01 -3.59 (m, 3H), 2.60 (brs, 1H), 2.56 -2.55 (m, 3H), 2.06 - 0.57 (m, 18H); hLPAi IC ₅₀ = 36 nM. Example 64 and scheme 7 87 δ ” ^Ν Λ 0 (1 S,3 S) -3 - ((6- (5 - ((isobutoxycarbonyl) amino) -1 -methyl- 1H-1,2,3 -triazol-4-yl) pyridine -3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 418.2; Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.25 (d, 7=2.4 Hz, 1H), 7.87 (d, 7=8.9 Hz, 1H), 7.51 (dd, 7=8.7, 2.6 Hz, 1H), 4.74 (br s, 1H), 3.86 (s, 3H), 2.58 (br d, 7=4.6 Hz, 1H), 2.56 - 2.55 (m, 3H), 1.95 - 1.43 (m, 9H), 1.04-0.51 ( m, 6H); hLPAi IC ₅₀ = 219hM. Example 64 and scheme 7 88 Q with ° 4=/ V ² LCMS, [M + H] ⁺ = 432.2; Ή NMR (500 MHz, DMSO-de) δ 8.28 (d, 7=2.4 Hz, 1H), 7.88 (d, 7=8.5 Hz, 1H), 7.52 (dd, 7=8.7, 2.6 Hz, 1H), 4.75 (br s, 1H), 4.01 (brs, 1H), 3.87 (s, 3H), 2.61 (brd, 7=3.7 Hz, 1H), 2.56 -2.55 (m, 2H), 1.97 - 1.83 (m, 2H) , 1.75 Example 64 and scheme 7

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(1 S,3 S)-3 -((6-( 1 -methyl-5 -(((pentyloxy)carbonyl)amino)- 1H-1,2,3-triazol-4yl) pyridin-3 -yl)oxy )cyclohexane-1 carboxylic acid (br s, 2Н), 1.70–1.47 (br, 6Н), 1.25 (brd, 7=8.2 Hz, ZN), 0.82 (br s, ZN); hLPAi IC ₅₀ = 34 nM. 89 /A ό ° ^Ν - \ 0 (1 S,3 S) -3 - ((6- (5 - ((butoxycarbonyl) amino) -1 -methyl-1 Η-1,2,3 -triazo l-4yl) pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 418.2; Ή NMR (500 MHz, DMSO-de) δ 8.51 - 8.09 (m, 1H), 7.98 - 7.25 (m, 2H), 4.75 (br s, 1H), 4.143.91 (m, 2H), 3.89-3.79 ( m, 3H), 2.69–2.59 (m, 3H), 1.88 (brs, 2H), 1.73 (brs, 3H), 1.68–1.51 (m, 6H), 0.84 (brs, 3H); hLPAi IC ₅₀ = 66 nM. Example 64 and scheme 7 90 /A ά ^{he is} Hell. ^Ν Λ O θ (1 S,3 S) -3 - ((6- (5 - (((cyclopentyloxy) carbonyl) amino) -1 -methyl-1 Η-1,2,3 triazol-4-yl) pyridine -3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 430.1; 'HNMR (500 MHz, DMSO-d ₆ ) δ 9.45 - 9.28 (m, 1H), 8.52-8.10 (m, 1H), 7.88 (br d, 7=8.9 Hz, 1H), 7.52 (dd, 7=8.9 , 2.4 Hz, 1H), 5.07–4.90 (m, 1H), 4.77 (br s, 1H), 3.87 (s, 3H), 2.73–2.62 (m, 1H), 2.58–2.56 (m, 2H), 2.03 - 1.92 (m, 1H), 1.891.39 (m, 13H); hLPAi IC ₅₀ = 149 nM. Example 64 and scheme 7 91 ά ° ⁿ ΑγθνΌ N- \ J (1 S,3 S) -3 - ((6- ( 1 -methyl-5 - ((((R) -1 phenylethoxy) carbonyl) amino) -1H-1,2, 3triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 465.9; 'HNMR (500 MHz, DMSO-de) δ 8.19 (br s, 1H), 7.86 (d, 7=8.9 Hz, 1H), 7.49 (br dd, 7=8.7, 2.6 Hz, 1H), 7.43 - 7.28 ( m, 4H), 5.99-5.62 (m, 1H), 4.75 (brs, 1H), 3.91 (s, 1H), 3.86 (s, 2H), 2.67 (br s, 1H), 2.58 - 2.55 (m, 3H ), 2.00-1.92 (m, 1H), 1.891.74 (m, 3H), 1.72-1.46 (m, 6H); hLPAi IC ₅₀ = 35 nM. Example 64 and scheme 7

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92 A___ Az Ν-Ν H ° \ (1 S,3 S)-3 -((6-(5 -((((benzyloxy) carbonyl)amino) methyl) -1 -methyl- 1H-1,2,3triazo l-4 -yl) -2 - (trifluoromethyl) pyridin-3 yl) oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 534.0; Ή NMR (DMSO-de) δ: 8.25 (brd, J=8.5 Hz, 1H), 7.93 (brd, J=8.5 Hz, 1H), 7.53 (brs, 1H), 7.16-7.43 (m, 5H), 5.01 (m, 3H), 4.80 (br d, J=4.6 Hz, 2H), 4.06 (brs, 3H), 2.5 5 (m, 1H), 1.20-2.15 (m, 8H); hLPAi IC ₅₀ = 14 hM. Example 1 93 „ΛΥ,,,ΟΗ ? A/s About Gy Ν-Ν Η O \ (18.38)-3-((6-(5-(((isobutoxycarbonyl)amino)methyl)-1-methyl-1 Η-1,2,3triazol-4-yl)-2-(trifluoromethyl)pyr id in-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 500.0; SNMR (DMSO-de) δ: 8.25 (brd, 1=8.9Hz, 1H), 7.94 (brd, 1=8.9Hz, 1H), 7.35 (brs, 1H), 5.00 (brs, 2H), 4.75 (brs , 2H), 4.06 (s, 3H), 3.09-3.82 (m, 1H), 2.56-2.62 (m, 1H), 1.352.14 (m, 9H), 0.82 (br d, J=4.9 Hz, 6H) ; hLPAi IC ₅₀ = 25 hM. Example 1 94 Ό _Υ ° ^Η A - Ν-Ν H ° \ ⁴ (18.38) -3- ((6- (5- (((butoxycarbonyl) amino) methyl) -1-methyl-1H-1,2,3 -triazol-4yl)-2-(trifluoromethyl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 499.8; SNMR (DMSO-de) δ: 8.25 (d, J=8.9Hz, 1H), 7.94 (brd, 1=8.9Hz, 1H), 7.32 (brs, 1H), 5.00 (brs, 2H), 4.75 (brs , 2H), 4.06 (s, 3H), 3.92 (brs, 1H), 2.56–2.62 (m, 1H), 1.182.15 (m, 12H), 0.84 (brs, 3H); hLPAi IC ₅₀ = 14 hM. Example 1 95 A / OH A / ^cf \u003d ⁰ k Ν-Ν Η O \ (1 S,3 S) -3 - ((6- ( 1 -methyl-5 - (((propoxy carbonyl) amino) methyl) - 1H-1 ,2,3 -triazole- LCMS, [M + H] ⁺ = 486.1; SNMR (DMSO-de) δ: 8.25 (d, J=8.9Hz, 1H), 7.94 (brd, 1=8.9Hz, 1H), 7.34 (brs, 1H), 5.01 (brs, 1H), 4.76 (brs , 2H), 4.07 (s, 3H), 3.88 (brs, 2H), 2.58 (brs, 1H), 1.14–2.17 (m, 10H), 0.83 (brs, 3H); hLPAi IC ₅₀ = 867 hM. Example 1

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4-yl)-2-(trifluoromethyl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid 96 L (G xL - NN Η ° X ^x \ 1 S,3 S) -3 - ((6- (5 - ((((cyclopentyloxy) carbonyl) amino) methyl) -1 -methyl-1H-1,2, 3triazo l-4 -yl) -2 - (trifluoromethyl) pyride in-3 yl) oxy) cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 512.0; Ή NMR (DMSO-de) δ: 8.25 (brd, 1=8.9Hz, 1H), 7.94 (brd, J=9.2Hz, 1H), 7.27 (brt, J=5.3Hz, 1H), 4.96-5.10 ( m, 1H), 4.834.96 (m, 1H), 4.57-4.80 (m, 2H), 4.06 (s, 3H), 2.562.63 (m, 1H), 0.95-2.17 (m, 16H); hLPAi IC ₅₀ = 33 hM. Example 1 97 A " ^CF 3 ⁰ X" NN H ° ^^X^F \ (1 S,3 S) -3 - ((6- (5 - ((((4-fluorobutoxy) carbonyl) amino) methyl) -1 - methyl-1 Η-1,2,3triazo l-4 -yl) -2 - (trifluoromethyl) pyridin-3 yl) oxy) cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 518.2; Ή NMR (METHANOL-d ₄ ) δ: 8.27 (d, J=8.8 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 4.68-5.05 (m, 1H), 4.294.52 (m,4H ), 4.19 (s, 3H), 4.06 (brt, J=5.8 Hz, 2H), 2.73 (brt, J=10.2 Hz, 1H), 1.38-2.30 (m, 12H); hLPAi IC ₅₀ = 25 hM. Example 1 98 Ag O N-N^ H O (1 S,3 S)-3 -((6-(5 -((((benzyloxy)carbonyl)amino)methyl)-1-methyl- 1H-1,2,3triazol-4-yl)-2-( difluoromethyl)pyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 516.2; Ή NMR (DMSO-de) δ: 8.16 (brd, J=8.5 Hz, 1H), 7.82 (brd, J=8.5 Hz, 1H), 7.54 (brs, 1H), 6.97-7.43 (m, 6H), 5.02 (s, 2H), 4.93 (br s, 1H), 4.77 (br d, J=4.9 Hz, 2H), 4.09 (s, 3H), 2.66 (brt, J=10.8 Hz, 1H), 1.322.17 ( m, 8H); hLPAi IC ₅₀ = 33 hM. Example 1

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99 Λ___λ,,/ΟΗ HF ₂ C^k O I ° v LuAL (1 S,3 S)-3 -((2-(difluoromethyl)-6-(5 (((isobutoxycarbonyl)amino)methyl)-1 methyl- 1Н-1,2,3-triazol-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 482.1; Ή NMR (DMSO-de) δ: 7.88 (brd, 1=8.4Hz, 1H), 7.64 (brd, 1=8.2Hz, 1H), 6.99-7.44 (m, 1H), 4.65 (br dd, J=11.7 , 4.8 Hz, 4H), 3.36–3.81 (m, 5H), 2.632.80 (m, 1H), 0.98–2.24 (m, 15H); hLPAi IC ₅₀ = 71 nM. Example 1 100 ΛΑ _ζ/ 0Η 9 ^ f HFzC^Z O \(18.38)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazole -4yl) -2 -(difluoromethyl)pyride in-3 yl)oxy)cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 482.3; NMR (DMSO-de) δ: 8.16 (brd, 1=8.9Hz, 1H), 7.83 (d, J=8.9Hz, 1H), 7.35 (brs, 1H), 7.01-7.28 (m, 1H), 4.94 ( br s, 1H), 4.72 (br d, J=4.3 Hz, 2H), 4.10 (s, 3H), 3.94 (br s, 2H), 2.67(brt, 1=10.7Hz, 1H), 1.17-2.18 ( m, 12H), 0.86 (brt, J=6.7 Hz, ZN); hLPAi IC ₅₀ = 39 nM. Example 1 101 L___Λ/ΟΗ if hf ₂ c,A. O I ° SPA-- \ (1 S,3 S) -3 - ((2- (difluoromethyl) -6- ( 1 -methyl-5 (((propoxycarbonyl) amino) methyl) -1H1,2,3 -triazole -4-yl) pyride in-3 yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 468.2; NMR (DMSO-de) δ: 8.16 (brd, J=8.8 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.36 (brs, 1H), 6.97-7.30 (m, 1H), 4.94 ( br s, 1H), 4.72 (br d, J=4.6 Hz, 2H), 4.10 (s, 3H), 3.90 (br d, J=8.2 Hz, 2H), 2.67 (brt, J=10.8 Hz, 1H) , 1.33-2.15 (m, 10H), 0.84 (brt, J=6.9 Hz, ZN); hLPAi IC ₅₀ = 2025 nM. Example 1 102 Ό _γ °Η 0 ° λ "9 \ (1 S,3 S) -3 - ((6- (5 - ((((benzyloxy) carbonyl) amino) methyl) -1 -methyl- 1H-1,2 ,3- LCMS, [M + H] ⁺ = 510.3; 'HNMR (DMSO-de) δ: 7.95 (brd, J=8.5 Hz, 1H), 7.85 (brs, 1H), 7.60 (brd, J=8.5 Hz, 1H), 7.27-7.42 (m, 5H), 5.02 (s, 2H), 4.83 (br s, 1H), 4.49-4.73 (m, 7H), 4.12(s, 3H), 2.65 (br t, J=10.5 Hz, 1H), 1.332.16 (m, 8H ); hLPAi IC ₅₀ = 30 nM. Example 1

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triazol-4-yl)-2-(methoxymethyl)pyridin-3yl)oxy)cyclohexane-1-carboxylic acid 103 X___X/OH ? - &° h a ° Ν-ΝIT \ ο Γ CI (lS,3S)-3-((6-(5-(2-((((2-xnopbenzyl)oxy)carbonyl)amino)ethyl)-1 methyl-1 Η-1,2,3-triazo l- 4-yl) -2 methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 528.3; Ή NMR (500 MHz, DMSO-de) δ 7.83 (br d, 7=8.2 Hz, 1H), 7.74 - 7.65 (m, 1H), 7.55 - 7.44 (m, 2H), 7.37 (br d, 7=7.3 Hz, 3H), 5.06 (s, 2H), 4.77 (br s, 1H), 3.98 (s, 3H), 3.53 3.15 (m, 3H), 2.64 (br d, 7=3.7 Hz, lH), 2.56( s, 1H), 2.45 (s, 3H), 2.09 1.42 (m, 8H); hLPAi IC ₅₀ = 595 nM. Example 1 and circuit 1 through interm, conn. 7 104 A___X/OH ? y A/ o ίγΝ h:m^ ° / Ν-Ν G X—V \ O ^X (18.38)-3-((2-methyl-6-(1-methyl-5-(2(((peopentyloxy )carbonyl)amino)ethyl)- 1H-1,2,3-triazol-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 474.3; 'HNMR (500 MHz, DMSO-d ₆ ) δ 7.83 (d, 7=8.5 Hz, 1H), 7.48 (brd, 7=8.2 Hz, 2H), 4.78 (br s, 1H), 4.00 (s, 3H) , 3.61 (s, 3H), 3.39–3.22 (m, 6H), 2.74–2.56 (m, 1H), 2.02 (br s, 1H), 1.94–1.40 (m, 7H), 0.84 (s, 9H); hLPAi IC ₅₀ = 1364 nM. Example 1 and circuit 1 through interm, conn. 7 105 -XJ -, /OH Ax / ⁰ N ~ N K A ⁴ ° X / (1 S,3 S) -3 - ((6- (5 - (2- (((cyclopentyloxy) carbonyl) amino) ethyl) -1-methyl-1H1,2,3-triazol-4-yl)-2-methyl-pyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 472.3; Ή NMR (500 MHz, DMSO-d ₆ ) δ 7.81 (brd, 7=8.5 Hz, 1H), 7.47 (d, 7=8.9 Hz, 1H), 7.38 (brs, 1H), 4.97-4.68 (m, 2H ), 3.99 (s, 3H), 3.42-3.13 (m, 2H), 2.64 (br s, 1H), 2.56 (s, 3H), 2.45 (s, 3H), 2.10-1.39 (m, 15H); hLPAi IC ₅₀ = 1833 nM. Example 1 and circuit 1 through interm, conn. 7 106 ^XJ-^/OH ? y Ax / ⁰ Xn n XX Ν-Ν Y \ O (1 S,3 S) -3 - ((6- (5 - (2- (((benzyloxy) carbonyl) amino) ethyl) -1 -methyl- 1H -1,2,3triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 493.9; ΉΉΜΡ (500 MHz, DMSO-de) δ 7.93 - 7.74 (m, 1H), 7.63 (br s, 1H), 7.57-7.41 (m, 1H), 7.40 7.20 (m, 4H), 4.98 (s, 2H) , 4.82-4.60 (m, 1H), 4.08 3.78 (m, 3H), 3.51-3.20 (m, 2H), 3.00 (s, 1H), 2.56 (s, 3H), 2.43 -2.36 (m, 2H), 1.77-1.43 (m, 5H), 1.33-1.10 (m, 2H), 0.78 (br d, 7=6.1 Hz, 2H); hLPAi IC ₅₀ = 525 nM. Example 1 and circuit 1 through interm, conn. 7 107 /X/Λ, /OH Ax/ o (/N H CHA^ _{Ao h} Ν-Ν G \ O (18.38)-3-((6-(5-(2-((butoxycarbonyl)amino)ethyl) -1-methyl- 1H-1,2,3triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.3; 'HNMR (500 MHz, DMSO-d ₆ ) δ 7.81 (brd, 7=8.5 Hz, 1H), 7.48 (d, 7=8.5 Hz, 1H), 7.43 (br s, 1H), 4.77 (br s, 1H ), 3.99 (s, 3H), 3.88 (brt, 7=6.4Hz, 1H), 3.42-3.21 (m, 3H), 2.64 (brt,7=10.4Hz, 1H), 2.55 (s, 2H), 2.45 (s, 3H), 2.10-1.96 (m, 1H), 1.90-1.74 (m, 3H), 1.691.40 (m, 6H), 1.33 - 1.20 (m, 2H), 0.86 (brt,7=7.2 Hz , ZN); hLPAi IC ₅₀ = 1464 nM. Example 1 and circuit 1 through interm, conn. 7

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Example 108 (1S,3S)-3-((6-(5-((3-(Cyclobutylmethyl)-3-methylureido)methyl)-1-methyl-1H-1,2,3triazol-4-yl)- 2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid

108A. (Cyclobutylmethyl)(methyl)carbamic acid acid chloride O

To a solution of triphosgene (269 mg, 0.91 mmol) in CH ₂ Cl ₂ (5 ml) at 0°C was added dropwise a solution of 1-cyclobutyl-N-methylmethanamine (150 mg, 1.51 mmol) and pyridine (183 μl , 2.27 mmol) in CH ₂ Cl ₂ (3 ml). The reaction mixture was allowed to warm to room temperature over 30 min, then quenched by the careful addition of 0.1N. HCl (5 ml). The aqueous phase was extracted with CH ₂ Cl ₂ (2x5 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (239 mg, 1.48 mmol, 98% yield) as a yellow oil which was used in the next step without further purification.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.57-3.44 (m, 2H), 3.14-3.00 (m, 3H), 2.66 (dt, J=15.7, 7.8 Hz, 1H), 2.172.04 (m, 2H ), 2.02–1.73 (m, 4H).

108V. (18.38)-Isopropyl 3-((6-(5-((3-(cyclobutylmethyl)-3-methylureido)methyl)-1-methyl-1H-1,2,3triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexanecarboxylate

The compound of example 108A (18 mg, 0.11 mmol) was added to a solution of the compound of example 1H (28 mg, 0.072 mmol) and TEA (12 μl, 0.087 mmol) in CH ₂ Cl ₂ (1 ml) at 0°C with followed by the addition of DMAP (1 mg, 7 μmol). After 10 min at 0° C., the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h, then concentrated in vacuo. The crude product was chromatographed (4 g SiO ₂ ; continuous gradient from 0 to 100% EtOAc/hexane over 10 min) to give the title compound (35 mg, 0.068 mmol, 94% yield) as a clear oil.

1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.5 Hz, 1H), 7.32-7.27 (m, 1H), 6.92 (br t, J=6.1 Hz, 1H), 5.05 (quin, J=6.3 Hz, 1H), 4.75-4.69 (m, 1H), 4.60 (d, J=6.3 Hz, 2H), 4.28 (s, 3H), 3.24 (d, J=7.2 Hz, 2H), 2.87-2.74 (m , 4H), 2.55 (s, 3Н), 2.48 (dt, J=15.5, 7.9 Hz, 1H), 2.14-2.07 (m, 1H), 2.03-1.58 (m, 13H), 1.29-1.24 (m, 6H ).

Example 108.

A mixture of the compound of example 108B (32 mg, 0.062 mmol) and aqueous 1.0 M NaOH solution (0.31 ml, 0.31 mmol) in THF (1 ml) was stirred at 45°C for 18 h, then cooled to room temperature and acidified to pH 4 with TFA and concentrated in vacuo. The crude product was purified by preparative HPLC (Sunfire C18 30x100 mm column; detection at 220 nm; flow rate: 40 ml/min; continuous gradient from 30% B to 100% B over 10 min + 2 min retention time at 100% B, where A = 90:10:0.1 H ₂ O:MeCN:TFA and B = 90:10:0.1 MeCN:H ₂ O:TFA) to give the title compound (TFA salt; 35 mg, 0.059 mmol, 94% yield as pure oil.

1Н NMR (500 MHz, CDCl3) δ 8.21 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 4.91 (br. s., 1H), 4.55 (s, 2H), 4.21 (s, 3H), 3.34 (d, J=7.2 Hz, 2H), 3.00-2.85 (m, 4H), 2.80 (s, 3H), 2.56 (dt, J=15.2, 7.7 Hz, 1H), 2.26 -2.12 (m, 1H), 2.09-1.62 (m, 14H);

[M+H] ⁺ = 471.1; hLPA1 IC ₅₀ = 82 nM.

Compounds according to the examples in the table. 4 was synthesized according to the procedures described for the compound of Example 108.

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Table 4

Etc. No. Structure and name Analytical and biological data 109 Am ⁰ Y O ^ν ~ ^ν \ n ι || 1 (1 S,3 S)-3 -((6-(5 -((3-benzyl-3-methyl ureido)methyl)-1 -methyl- 1H-1,2,3-triazol-4yl)-2 -methylpyride in-3 -yl) hydroxy) cyclohexanecarboxylic acid LCMS, [M+H] ⁺ = 493.1; Ή NMR (500 MHz, CDC13) b 8.21 (d, 7=9.1 Hz, 1H), 8.00 (d, 7=9.1 Hz, 1H), 7.44-7.11 (t, 5H), 4.89 (br. s., 1H) , 4.68 4.47 (t, 4H), 4.15(br.s., 3H), 2.98 (s, 3H), 2.88 (br. s., 1H), 2.73 (s, 3H), 2.26-2.12 (m, 1H ), 2.03 - 1.58 (m, 7H); hLPAi IC ₅₀ = 85 nM. BY Ό _Τ ° ^Η mah ° I o Ν-Ν^ Η N (18.38)-3-((2-methyl-6-(1-methyl-5-((3-methyl3-propylureido)methyl) -1 Η-1,2,3-triazol-4yl)pyridin-3-yl)oxy) cyclohexanecarboxylic acid LCMS, [M+H] ⁺ = 445.5; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.21 (d, 7=9.1 Hz, 1H), 8.00 (d, 7=9.1 Hz, 1H), 4.90 (br. s., 1H), 4.56 (s, 2H) , 4.22 (s, 3H), 3.26 (t, 7=7.3 Hz, 2H), 2.99-2.86 (m, 4H), 2.79 (s, 3H), 2.27 2.15 (m, 1H), 2.08 - 1.76 (m, 6H), 1.75-1.51 (m, 3H), 0.90 (t, 7=7.4 Hz, ZN); hLPAi IC ₅₀ = 217hM. 111 A; Ν-Ν^ H | (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -((3-methyl3-pentylureido)methyl)- 1H-1,2,3-triazol-4yl)pyridine- 3-yl) hydroxy) cyclohexanecarboxylic acid LCMS, [M+H] ⁺ = 473.4; ΉΉΜΡ (500 MHz, DMSO-de) δ 7.93 (br d, 7=7.0 Hz, 1H), 7.63 (brd, 7=8.5 Hz, 1H), 4.82 (brs, 1H), 4.54 (s, 2H), 4.11 (s, 3H), 3.64 (brs, lH), 3.10(brt, 7=7.3 Hz, 2H), 2.73 (s, 3H), 2.62 (brt, 7=10.7 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.92-1.72 (m, 3H), 1.70-1.44 (m, 5H), 1.341.23 (m, 2H), 1.20-0.98 (m, 5H), 0.74 (t, 7=7.3 Hz, ZN) ; hLPAi IC ₅₀ = 226 nM

Example 112 (1S,3S)-3-((6-(5-((3-Benzylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine- 3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt

112A. Methyl (1S,3S)-3-((6-(5-((3-benzylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylate

To a solution of methyl (1S,3 S)-3 -((6-(5-(aminomethyl)-1 -methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy )cyclohexane-1-carboxylate (synthesized analogously to the corresponding isopropyl ester of Example 1H, 30 mg, 0.083 mmol) in DCE (1.7 mL), Et ₃ N (29 μL, 0.21 mmol) was added followed by CDI ( 27.1 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 1 h, after which benzylamine (23 μl, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then heated at 80°C for 30 min, then cooled to room temperature. Water was added to the reaction mixture, which was neutralized to pH 7 with 1 M aq. HCl, then extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (41 mg, 100%) as a clear colorless residue. The product was used in the next step without further purification.

LCMS [M+H]+ = 493.4.

Example 112.

To a solution of the compound from example 112A (41 mg, 0.083 mmol) in THF (0.56 ml) was added 1.0 M aq. LiOH (0.42 ml, 0.42 mmol). The reaction mixture was stirred at room temperature for 23 h, then concentrated in vacuo. The residue was dissolved in 1:1 MeCN:H ₂ O (1.5 ml) and TFA was added to adjust the pH to 3. This product was purified by preparative HPLC (column: Sunfire Prep C18 OBD, 30x100 mm, particles 5 μm; mobile phase A: 10:90 MeCN: H ₂ O with 0.1% TF A; mobile phase B: 90:10 MeCN: H ₂ O with 0.1% TFA; gradient: 10-100% B over 10 min, then hold for 2 min at 100% B; flow rate: 40 ml/min) to give the title compound (10 mg, 20%) as a white solid.

LCMS [M+H] ⁺ = 479.4.

1H NMR (500 MHz, DMSO-d6 and D2O) δ 7.90 (d, J=8.5 Hz, 1H), 7.59 (br d, J=8.5 Hz, 1H), 7.30-7.25 (m, 2H), 7.23-7.16 (m, 3H), 4.81 (br s, 1H), 4.64 (s, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 2.67-2.59 (m, 1H), 2.49 (s, 3H) , 2.07-1.98 (m, 1H), 1.91-1.74 (m, 3H), 1.68-1.44 (m, 4H).

hLPA1 IC ₅₀ = 63 nM.

Example 113 (1S,3S)-3-((6-(5-((3-Benzyl-1-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl) -2methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt.

113A. Methyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3-yl)oxy )cyclohexane-1-carboxylate

To a solution of the aldehyde from example 64A (325 mg, 0.91 mmol) in MeOH (3.6 ml) at room temperature was added MeNH ₂ -HCl (92 mg, 1.36 mmol). The reaction mixture was stirred at room temperature for 20 min, then NaBH ₃ CN (85 mg, 1.36 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then partitioned between EtOAc and 1.0 M aq. K2HPO4. The aqueous layer was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a viscous yellow oil. The residue was chromatographed (SiO ₂ ; continuous gradient 0-10% MeOH/CH ₂ Cl ₂ ) to give the title compound (180 mg, 53%) as a clear colorless oil.

LCMS [M+H] ⁺ = 374.2.

1H NMR (500 MHz, CD3OD) δ 7.89 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.84-4.79 (m, 1H), 4.16 (s, 3H), 4.09 (s, 2H), 3.70 (s, 3H), 2.89-2.82 (m, 1H), 2.53 (s, 3H), 2.46 (s, 3H), 2.19-2.09 (m, 1H), 2.01-1.90 (m , 3H), 1.82–1.61 (m, 4H).

113V. Methyl (1S,3S)-3-((6-(5-((3-benzyl-1-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2methylpyridin- 3-yl)oxy)cyclohexane-1-carboxylate

To a solution of the compound of example 113A (20 mg, 0.054 mmol) in DCE (1.1 ml) was added Et ₃ N (52 μl, 0.38 mmol) followed by triphosgene (24 mg, 0.080 mmol). The reaction mixture was stirred at 0°C for 30 min; then benzylamine (35 μl, 0.32 mmol) was added. The reaction mixture was allowed to warm to room temperature (a white precipitate formed over time) and stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and 0.5

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M aq. HCl. The aqueous layer was extracted with EtOAc (2x). The combined organic extracts were washed with 1.0 M aq. K ₂ HPO ₄ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (27 mg, 100%) as a clear pale yellow oil. This product was used in the next step without further purification.

LCMS [M+H]+ = 507.4.

Example 113.

To a solution of the compound from example 113B (27 mg, 0.053 mmol) in THF (0.36 ml) was added 1.0 M aq. LiOH (0.27 ml, 0.27 mmol). The reaction mixture was stirred at room temperature for 18.5 h, then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2 times) and these combined organic extracts were discarded. The aqueous layer was acidified with 1N. aq. HCl to pH 5 and then extracted with EtOAc (3 times). These combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Preparative HPLC purification (column: Sunfire Prep C18 OBD, 30x100 mm, 5 µm particles; mobile phase A: 10:90 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 90:10 MeCN:H ₂ O with 0.1% TFA; gradient: 15-100% B over 10 min, then hold for 2 min at 100% B; flow rate: 40 ml/min) provided the title compound (8 mg, 25%) as a white solid.

LCMS [M+H] ⁺ = 493.3.

1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.33-7.26 (m, 2H), 7.267.13 (m, 4Н), 5.13 (s, 2Н), 4.82-4.74 (m, 1H), 4.27 (d, J=5.5 Hz, 2Н), 3.99 (s, 3Н), 2.83 (s, 3Н), 2.71-2.58 (m , 1H), 2.43 (s, 3H), 2.09-1.97 (m, 1H), 1.92-1.74 (m, 3H), 1.70-1.44 (m, 4H).

31 out of 32 protons detected, acidic proton missing. hLPA1 IC ₅₀ = 218 nM.

Compounds according to the examples in the table. 5 was synthesized according to the procedures described for the compounds of examples 112 and 113.

Table 5

Etc. No. Structure and name Analytical and biological data Method 114 /HE ° n 1 I o γ A N-γ n Nmm (18.38)-3-((6-(5-((3-(2-cyclopropylethyl)-3-methylureido)methyl)-1-methyl1H-1,2,3-triazol-4-yl)-2 - methylpyridin-3-yl)oxy)cyclohexane 1-carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 471.3; SH NMR (500 MHz, DMSO-de and D ₂ O) δ 7.96 (d, 7=8.8 Hz, 1H), 7.75 (brd, 7=7.4 Hz, 1H), 4.87 (br s, 1H), 4.55 (s ,2H), 4.11 (s, 3H), 3.25 - 3.17 (m, 2H), 2.77 (s, 3H), 2.68 - 2.59 (m, 1H), 2.54 (s, 3H), 2.09 - 1.99 (m, 1H ), 1.92 - 1.75 (m, 3H), 1.70 - 1.44 (m, 4H), 1.25 (q, 7=7.2 Hz, 2H), 0.56 -0.45 (m, 1H), 0.31 -0.24 (m, 2H), -0.05--0.13 (m, 2H); hLPAi IC ₅₀ = 112hM. Example 112 115 _L ADn/OH (18.38)-3-((6-(5-((3-benzyl-1,3dimethylureido)methyl)-1-methyl-1H1,2,3-triazo l-4-yl) -2-methyl-pyridin3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 507.3; Ή NMR (500 MHz, DMSO-de) δ 7.85 (d, 7=8.5 Hz, 1H), 7.50 (d, 7=8.5 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.27 - 7.22 (m, 1H), 7.20 7.16 (m, 2H), 4.91 (s, 2H), 4.81 4.74 (m, 1H), 4.28 (s, 2H), 4.01 (s, 3H), 2.74 (s, 3H), 2.68 -2.59 (m, 1H), 2.58 (s, 3H), 2.45 (s, 3H), 2.06 - 1.97 (m, 1H), 1.91 1.74 (m, 3H), 1.68 - 1.45 (m, 4H). Omitted acidic proton; hLPAi IC ₅₀ = 166 nM. Example 113 116 ,-ΑΑ',/ΟΗ Ϋ° Ν-Ν\ Η Ν mm (1 S,3 S)-3 -((6-(5 -((3-isopentyl-3 methyl-ureido)methyl)-1 -methyl- 1H-1,2,3triazo l-4 -yl) -2 -methylpyride in-3 yl)oxy)cyclohexane-1 -carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 473.2; Ή NMR (500 MHz, DMSO-de) δ 7.91 (d, 7=8.5 Hz, 1H), 7.60 (br d, 7=8.5 Hz, 1H), 4.81 (br s, 1H), 4.56 (s,2H) , 4.10 (s, 3H), 3.163.06 (m, 2H), 2.72 (s, 3H), 2.68 2.58 (m, 1H), 2.50 (s, 3H), 2.101.96 (m, 1H), 1.94- 1.74 (m, 3H), 1.69 - 1.43 (m, 4H), 1.41 1.29 (m, 1H), 1.23 - 1.11 (m, 2H), 0.75 (d, 7=6.4 Hz, 6H). 34 out of 36 protons detected; hLPAi IC ₅₀ = 92 hM. Example 112

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117 ^DA , .one ⁰ ιι 1 I ⁰ Ν-Ν Η Ν \ ⁿ (1 S,3 S)-3 -((6-(5 -((3 -(bicyclo [2.2.1] heptane-2 -yl)ureido)methyl)-1-methyl1H-1,2,3-triazol-4-yl)-2methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt (diastereomeric mixture) LCMS, [M + H] ⁺ = 483.4; Ή NMR (500 MHz, DMSO-de) δ 7.87 - 7.82 (m, 7=8.5 Hz, 1H), 7.47 (d, 7=8.6 Hz, 1H), 4.75 (br s, 1H), 4.70 - 4.59 (m , 2H), 4.09 (s, 3H), 3.80 -3.67 (m, 1H), 2.66 -2.57(m, 1H), 2.48 (s, 3H), 2.20 -2.11 (m, 1H), 2.09 - 1.93 (m , 2H), 1.89–1.74 (m, 4H), 1.701.37 (m, 6H), 1.34–1.14 (m, 3H), 1.14–1.02 (m, 1H), 0.68–0.51 (m, 1H). 31 out of 34 protons detected; hLPAi 1 IC ₅₀ = 420 hM. Example 112 118 /V d ⁰ Ν-Ν Η Ν γγ \ ^Η (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -((3-(2methylbutyl)ureido)methyl)- 1H -1,2,3triazol-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) LCMS, [M + H] ⁺ = 459.4; Ή NMR (500 MHz, DMSO-de) δ 7.85 (d, 7=8.5 Hz, 1H), 7.48 (d, 7=8.5 Hz, 1H), 4.78 (brs, 1H), 4.65 - 4.55 (m, 2H) , 4.09 (s, 3H), 2.92 - 2.84 (m, 1H), 2.80 - 2.72 (m, 1H), 2.66 - 2.57 (m, 1H), 2.47 (s, 3H), 2.06 - 1.95 (m, 1H) , 1.93 - 1.72 (m, 3H), 1.68 - 1.40 (m, 4H), 1.37 - 1.11 (m, 2H), 1.02 - 0.88 (m, 1H), 0.82 - 0.66 (m, 6H). Found from 34 protons; hLPAi IC ₅₀ = 105 nM. Example 112 119 -DD „/OH ? if th ° , Dl A ^ν λ ⁿ n m (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 - ((3-( 1 phenylbutyl) ureido) methyl) - 1H -1,2,3triazol-4-yl)pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA ol (diastereomeric mixture) LCMS, [M + H] ⁺ = 521.5; Ή NMR (500 MHz, DMSO-de) δ 7.86 (d, 7=8.5 Hz, 1H), 7.52 (d, 7=8.9 Hz, 1H), 7.28 -7.13 (m, 5H), 4.79 (br s, 1H ), 4.66-4.51 (m, 3H), 4.08 -3.99 (m, 3H), 2.67 - 2.57 (m, 1H), 2.47 (s, 3H), 2.07 - 1.96 (m, 1H), 1.90-1.72 (m , 3H), 1.68 - 1.42 (m, 6H), 1.23 - 1.04 (m, 2H), 0.78 (brt, 7=7.3 Hz, ZN). 33 out of 36 protons detected; hLPAi IC ₅₀ = 187 nM. Example 112

- 93 042829

(1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -((3-(1 phenylpropyl)ureido)methyl)-1H-1,2,3triazol-4-yl) pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt (diastereomeric mixture)

(18.38)-3-((6-(5-((3-(2-fluoro-1-phenylethyl)ureido)methyl) -1-methyl-1 Η-1,2,3 triazol-4 -yl ) -2-methylpyride in-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt (diastereomeric mixture)

(18.38)-3-((6-(5-((3-isopentyl-ureido)methyl)-1-methyl-1 Η-1,2,3-triazol-4-yl) 2-methylpyridin-3 -yl) hydroxy) cyclohexane-1-carboxylic acid, TFA salt

LCMS, [M + H] ⁺ = 507.4;

Ή NMR (500 MHz, DMSO-de) δ 7.89 (d, 7=8.5 Hz, 1H), 7.56 (br d, 7=8.5 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.19 (br d, 7=6.7 Hz, 3H), 4.81 (br s, 1H), 4.61 (br s, 2H), 4.53 - 4.44 (m, 1H), 4.06 (s, 3H), 2.67 -2.60 (m, 1H), 2.09 - 1.98 (m, 1H), 1.92 - 1.74 (m, 3H), 1.69-1.44 (m, 6H), 0.74 (brt, 7=7.2 Hz, ZN). 28 out of 34 protons detected;

hLPAi IC ₅₀ = 23 8 hM.

LCMS, [M + H] ⁺ = 511.4;

Ή NMR (500 MHz, DMSO-de) δ 7.93 - 7.84 (m, 1H), 7.57 - 7.49 (m, 1H), 7.33 - 7.23 (m, 5H), 5.00 -4.86 (m, 1H), 4.79 (br s, 1H), 4.68 -4.37 (m, 4H), 3.89 3.71 (m, 3H), 2.66 -2.58 (m, 1H), 2.48 (s, 3H), 2.07 - 1.95 (m, 1H), 1.93 - 1.71 (m, 3H), 1.68 1.41 (m, 4H). 28 out of 31 protons found;

hLPAi IC ₅₀ = 5 5 5 hM.

LCMS, [M + H] ⁺ = 459.4;

Ή NMR (500 MHz, DMSO-de) δ 7.90 (brd, 7=8.9 Hz, 1H), 7.61 (brd, 7=8.5 Hz, 1H), 4.82 (brs, lH), 4.59(s, 2H), 4.10 (s, 3H), 2.96 (brt,7=7.2Hz, 2H), 2.62 (brt, 7=10.4Hz, 1H), 2.07-1.98 (m, 1H), 1.92 - 1.73 (m, 3H), 1.71 - 1.41 (m, 5H), 1.24-1.14 (m, 2H), 0.80 (d, 7=6.4 Hz, 6H). 28 out of 34 protons detected;

hLPAi IC ₅₀ = 101 nM.

Example 112

Example 112

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123 Ό _υ ° ^η NN Η N \ ri (lS,3S)-3-((6-(5-((3-((3,3-difluorocyclobutyl)methyl)ureido)methyl)-1 -methyl-1 Η- 1,2,3-triazol-4-yl) 2-methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 493.4; Ή NMR (500 MHz, DMSO-de) δ 7.92 (d, 7=8.5 Hz, 1H), 7.65 (br d, 7=8.9 Hz, 1H), 4.83 (br s, 1H), 4.59 (s, 2H) , 4.09 (s, 3H), 3.11 3.04 (m, 1H), 2.67 -2.58 (m, 1H), 2.26-2.11 (m, 3H), 2.07 1.98 (m, 1H), 1.93 - 1.73 (m, 3H) , 1.67 - 1.43 (m, 4H). 21 out of 30 protons detected; hLPAi IC ₅₀ = 929 hM. Example 112 124 /OH γ y ° Ν-Ν Η Ν \ ⁿ (18.38)-3-((6-(5-((3-butylureido) methyl)-1-methyl-1 Η-1,2,3-triazole -4 -yl) 2-methylpyride in-3 yl) oxy) cyclohexane-1 -carboxylic acid, TFA LCMS, [M + H] ⁺ = 445.4; Ή NMR (500 MHz, DMSO-de) δ 7.90 (brd, 7=8.5 Hz, 1H), 7.61 (br d, 7=8.9 Hz, 1H), 4.82 (br s, 1H), 4.59 (s, 2H) ,4.10(s, 3H), 2.95 (br t, 7=6.7 Hz, 2H), 2.73 2.58 (m, 1H), 2.07 - 1.97 (m, 1H), 1.92 - 1.73 (m, 3H), 1.691.42 (m, 4H), 1.34 - 1.24 (m, 2H), 1.24-1.13 (m, 2H), 0.80 (t, 7=7.2 Hz, ZN). 26 out of 32 protons detected; hLPAi IC ₅₀ = 434 hM. Example 112 125 Lg ⁰ n 1 I ° n tuA 7 N-N \ Η N (1 S,3 S)-3 - ((2-methyl-6-( 1 -methyl-5 - ((3 methyl-3 - (3 - methylbutan-2-yl)ureido)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt (diastereomer 1) LCMS, [M + H] ⁺ = 473.4; Ή NMR (500 MHz, DMSO-de) δ 7.91 (d, 7=8.5 Hz, 1H), 7.60 (br d, 7=8.5 Hz, 1H), 4.82 (br s, 1H), 4.64 - 4.54 (m, 2H), 4.10 (s, 3H), 2.97 - 2.87 (m, 1H), 2.68 - 2.59 (m, 1H), 2.56 (br s, 3H), 2.09 1.97 (m, 1H), 1.93 - 1.74 (m, 3H), 1.68 - 1.45 (m, 5H), 0.96 (d, 7=6.7 Hz, SA), 0.81 (d, 7=6.4 Hz, SA), 0.57 (brd, 7=6.4 Hz, SA). 31 out of 36 protons detected; hLPAi 1C ₅₀ = 1.206 nM. Example 112

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126 DxD-,,/ΟΗ γ f γ ° Χύ j Ν-Ν Η Ν \ ^Η / (1 S,3 S)-3 -((2-methyl-6-( 1-methyl-5 -((3-( 3 methylbutan-2 -yl)ureide o)methyl) -1H1,2,3-triazol-4-yl)pyride in-3-yl)oxy) cyclohexane-1-carboxylic acid, TFA salt (diastereomer 2) LCMS, [M + H] ⁺ = 459.3; Ή NMR (500 MHz, DMSO-de) δ 7.88 (d, 7=8.5 Hz, 1H), 7.54 (d, 7=8.9 Hz, 1H), 4.8O (br s, 1H), 4.68 -4.59 (m, 2H), 4.11 (s, 3H), 2.97 - 2.88 (m, 1H), 2.67 - 2.59 (m, 1H), 2.50 (br s, 3H), 2.09 1.97 (m, 1H), 1.93 - 1.70 (m, 3H), 1.70 - 1.42 (m, 5H), 0.89 (d, 7=6.7 Hz, ZH), 0.76 (d, 7=6.7 Hz, 6H). 31 out of 34 protons detected; hLPAi 1C ₅ o = 611 nM. Example 112 127 A '|f O n η \ ^Η 1 (1S, 3 S)-3 -((6-(5 -((3-isobutylureido) methyl)-1 -methyl-1 Η-1,2,3 -triazole- 4-yl) 2-methylpyride in-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 445.3; Ή NMR (500 MHz, DMSO-de) δ 7.87 (d, 7=8.5 Hz, 1H), 7.53 (d, 7=8.9 Hz, 1H), 4.8O (br s, 1H), 4.62 (s, 2H) ,4.11 (s, 3H), 2.81 2.75 (m, 2H), 2.66 -2.58 (m, lH), 2.50(br s, 3H), 2.06-1.99 (m, 1H), 1.93 - 1.72 (m, 3H) , 1.69 - 1.43 (m, 5H), 0.76 (d, 7=6.7 Hz, 6H). 29 out of 32 protons detected; hLPAi IC ₅₀ = 2.270 nM. Example 112 128 h g f° Oh Ν—Ν^ Η Ν (1 S,3 S)-3 -((6-(5 -((3 -isobutyl-3 methylureido)methyl) -1 -methyl- 1H-1,2,3triazol-4 -yl) -2 -methylpyride in-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 459.3; ^1H NMR (500 MHz, DMSO-de) δ 7.87 (d, 7=8.5 Hz, 1H), 7.52 (d, 7=8.5 Hz, 1H), 6.71 (brt, 7=5.8 Hz, 1H), 4.79 ( br s, 1H), 4.58 (br d, 7=5.8 Hz, 2H), 4.10(s, 3H), 2.93 (br d, 7=7.3 Hz, 2H), 2.73 (s, 3H), 2.67 -2.58 ( m, 1H), 2.48 (s, 3H), 2.06 - 1.97 (m, 1H), 1.92 - 1.69 (m, 4H), 1.67 - 1.44 (m, 4H), 0.68 (d, 7=6.4 Hz, 6H) . 33 out of 34 protons detected; hLPAi IC ₅₀ = 273 hM. Example 112

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129 ^D „OH Ur J ° Aby (1 S,3 S)-3 -((2-methyl-6-( 1 -methyl-5 -((3-( 1 phenylethyl)ureido)methyl)-1 Η-1,2,3 triazo l-4 -yl) pyride in-3 yl) oxy) cyclohexane-1 -carboxylic acid, TFA (diastereomeric mixture) LCMS, [M + H] ⁺ = 493.4; Ή NMR (500 MHz, DMSO-de) δ 7.87 (d, 7=8.6 Hz, 1H), 7.51 (d, 7=8.7 Hz, 1H), 7.31 -7.16 (m, 5H), 4.81 -4.70 (m, 2H), 4.70 4.59 (m, 2H), 4.08 (s, 3H), 2.70 2.61 (m, 1H), 2.49 (s, 3H), 2.08 1.98 (m, 1H), 1.94 - 1.77 (m, 3H), 1.73 - 1.48 (m, 4H), 1.29 (d, 7=7.0 Hz, ZN). 29 out of 32 protons detected; hLPAi IC ₅₀ = 142 nM. Example 112 130 D\D„/OH ή ° Aq (1 S,3 S)-3 -((2-methyl-6-(1 -methyl-5 -((3 ((R) -1 -phenylethyl)ureido)methyl) -1H1,2,3-triazole- 4-yl) pyridin-3 yl) hydroxy) cyclohexane-1-carboxylic acid, TFA LCMS, [M + H] ⁺ = 493.2; Ή NMR (500 MHz, DMSO-de) δ 7.89 (d, 7=8.5 Hz, 1H), 7.58 (br d, 7=8.9 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.24-7.14 (m , 3H), 4.81 (br s, 1H), 4.74 - 4.65 (m, 1H), 4.64 - 4.54 (m, 2H), 4.07 (s, 3H), 2.67 - 2.59 (m, 1H), 2.50 (s, 3H), 2.07 - 1.97 (m, 1H), 1.92-1.73 (m, 3H), 1.69 - 1.45 (m, 4H), 1.26 (d, 7=7.0 Hz, ZN). 29 out of 32 protons detected; hLPAi 1C ₅₀ = 275 nM. Example 112 131 ^D___A,, „he j ; Λ (1 S,3 8)-3-((2-methyl-6-( 1-methyl-5 -((3 methyl-3-((R)-l- phenylethyl)ureido)methyl)-1 Η-1,2,3 triazo l-4-yl)pyride in-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA LCMS, [M + H] ⁺ = 507.3; Ή NMR (500 MHz, DMSO-de) δ 7.87 (d, 7=8.9 Hz, 1H), 7.49 (d, 7=8.9 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.21 -7.18 (m, 1H), 7.12 (br d, 7=7.6 Hz, 2H), 6.89 (br t, 7=5.6 Hz, 1H), 5.43 - 5.37 (m, 1H), 4.77 (br s, 1H), 4.73 - 4.60 ( m, 2H), 4.11 (s, 3H), 2.68-2.57 (m, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.05 - 1.94 (m, 1H), 1.91 1.69 (m, 3H ), 1.69-1.42 (m, 4H), 1.36 (d, 7=7.0 Hz, ZN). 33 out of 34 protons detected; hLPAi 1С ₅₀ = 217nM. Example 112

- 97 042829

132 yoon y ° (1S, 3 S) -3 - ((2-methyl-6-( 1 -methyl-5 - ((3 methyl-3- ((8) -1-phenylethyl) ureido) methyl) -1H-1,2 ,3-triazol-4yl)pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 507.4; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.16 (d, 7=9.1 Hz, 1H), 7.80 (brd, 7=8.8 Hz, 1H), 7.367.30 (m, 2H), 7.28 - 7.22 (br, 3H ), 5.69 - 5.54 (m, 1H), 4.85 -4.75 (m, 1H), 4.68 (s, 2H), 4.27 (s, 3H), 2.92-2.81 (t, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.22 -2.10 (t, 1H), 2.00 - 1.77 (t, 6H), 1.72-1.61 (t, 1H), 1.51 (d, 7=7.2 Hz, 3H). 32 out of 34 protons detected; hLPAi 1C ₅₀ = 276 nM. Example 112 133 Αγ Yun A ° chKHAD A Ν-Ν Η Ν X \ / (1 S,3 S)-3 -((6-(5 -((3 -(tert-butyl)-3methylureido)methyl)-1 -methyl- 1H-1,2,3triazol-4-yl)-2 -methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 459.0; Ή NMR (500 MHz, DMSO-de) δ 7.87 (brd, 7=8.5 Hz, 1H), 7.51 (br d, 7=8.7 Hz, 1H), 6.60 (br s, 1H), 4.77 (br s, 1H ), 4.67 - 4.55 (m, 2H), 4.18 - 4.03 (m, 3H), 2.76 - 2.67 (m, 3H), 2.67 - 2.58 (m, 1H), 2.48 (s, 3H), 2.05 - 1.95 (m , 1H), 1.89–1.75 (m, 3H), 1.71–1.48 (m, 4H), 1.28 (s, 6H). 30 out of 34 protons detected; hLPAi IC ₅₀ = 1.089 nM Example 112 134 JUN A ° λχ Ν-Ν _χ Η N x (18.38)-3-((6-(5-((3-isopropyl-3methylureido)methyl)-1-methyl- 1H-1,2,3triazole-4 -yl)-2-methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt LCMS, [M + H] ⁺ = 445.4; 'HNMR (500 MHz, DMSO-de) δ 7.88 (d, 7=8.5 Hz, 1H), 7.54 (d, 7=8.5 Hz, 1H), 4.79 (br s, 1H), 4.56 (s, 2H), 4.24-4.18 (m, 1H), 4.10 (s, 3H), 2.67 -2.59 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H), 2.05 1.99 (m, 1H), 1.92 - 1.73 (m, 3H), 1.67 - 1.42 (m, 4H), 0.94 (d, J=6.1 Hz, 6H). 30 out of 32 protons detected; hLPAi IC ₅₀ = 519 nM Example 112

Example 135 (1S,3S)-3-((6-(5-(3-Benzylureido)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy )cyclohexane-1-carboxylic acid, 1TFA

135A. Methyl (1S,3S)-3-((6-(5-(3-benzylureido)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy) cyclohexane-1-carboxylate, 1TFA

To a microwave treatment vessel containing a suspension of the compound of Example 64B (30 mg, 0.080 mmol) in toluene (0.80 ml) was added Et ₃ N (67 μl, 0.48 mmol) and (PhO)2PON ₃ (43 μl , 0.20 mmol). The reaction mixture was heated in a microwave reactor at 100°C for 1 h, then cooled to room temperature. Benzylamine (22 μl, 0.20 mmol) was added and the reaction mixture was heated in a microwave at 100° C. for 10 min, then cooled to room temperature. The reaction mixture was partitioned between EtOAc and 1.0 M aq. _{K2HPO4 .} The aqueous layer was extracted with EtOAc (2 times). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The clear, colorless residue was purified by preparative HPLC (column: Sunfire Prep C18 OBD, 30x100 mm, particles 5 µm; mobile phase A: 10:90 MeOH:H ₂ O with 0.1% TFA; mobile phase B: 90:10 MeOH: H ₂ O with 0.1% TFA gradient: 25-100% B over 10 min then hold for 2 min

- 98 042829 at 100% B; flow rate: 40 ml/min) to give the title compound (22 mg, 46%) as a clear colorless oil.

LCMS [M+H]+ = 479.3.

Example 135.

To a solution of the compound from example 135A (22 mg, 0.037 mmol) in THF (0.24 ml) was added 1.0 M aqueous LiOH solution (0.22 ml, 0.22 mmol). The reaction mixture was stirred at room temperature for 20 h, then concentrated in vacuo. The residue was dissolved in a mixture of 1:1 MeCN:H ₂ O (1.5 ml); TFA was added to adjust the pH to 3. This product was purified by preparative HPLC (column: Sunfire Prep C18 OBD, 30x100 mm, particles 5 μm; mobile phase A: 10:90 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 90:10 MeCN:H ₂ O with 0.1% TFA; gradient: 10-100% B over 10 min, then hold for 2 min at 100% B; flow rate: 40 ml/min) to give the title compound (13 mg, 61%) as a white solid.

LCMS [M+H]+ = 465.3.

'H NMR (500 MHz, CDCl3) δ 11.59-11.45 (m, 1H), 9.76-9.66 (m, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H ), 7.42-7.38 (m, 2H), 7.38-7.32 (m, 2H), 7.31-7.26 (m, 1H), 4.76-4.67 (m, 1H), 4.53 (br d, J=5.0 Hz, 2H) , 4.11 (s, 3Н), 2.89-2.82 (m, 1H), 2.26 (s, 3Н), 2.23-2.15 (m, 1H), 2.06-1.93 (m, 2H), 1.86-1.63 (m, 4H) , 1.63-1.52 (m, 1H).

27 out of 28 protons detected, acidic proton missing. hLPA1 IC ₅₀ = 329 nM.

Example 136 (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(3-((R)-1-phenylethyl)ureido)-1H-1,2,3- triazol-4yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, 1TFA

Example 136 was synthesized following the procedures described for Example 135.

LCMS [M+H]+ = 479.1.

¹ H NMR (500 MHz, DMSO-06) δ 8.48 (s, 1H), 7.80 (br d, J=7.9 Hz, 1H), 7.73 (br d, J=8.5 Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.39-7.26 (m, 4H), 7.25-7.19 (m, 1H), 4.86-4.73 (m, 2H), 3.84 (s, 3H), 2.69-2.59 (m, 1H) , 2.54 (s, 3H), 2.11-1.95 (m, 1H), 1.92-1.72 (m, 3H), 1.70-1.44 (m, 4H), 1.39 (br d, J=7.0 Hz, 3H).

The carboxylic acid proton was not observed. hLPA1 IC ₅₀ =103 nM.

Example 137 (1S,3S)-3-((6-(5-(((N-(Cyclopentylmethyl)-N-methylsulfamoyl)amino)methyl)-1-methyl1H-1,2,3-triazole-4- yl)-2-methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid

137A. (Cyclopentylmethyl)(methyl)sulfamoyl chloride

To a solution of 1.0 M sulfuryl chloride in CH ₂ Cl ₂ (514 μl, 0.51 mmol) in CH ₂ Cl ₂ (1 ml) was added a mixture of 1-cyclopentyl-N-methylmethanamine, HCl salt (77 mg, 0.51 mmol ) and TEA (179 μl, 1.29 mmol) in CH ₂ Cl ₂ (1 ml). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours to give the crude title compound, which was used in the next reaction without further purification.

137B. tert-Butyl (1 S,3 S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl )oxy)cyclohexane-1-carboxylate

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A mixture of (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy)cyclohexane- 1-carboxylic acid (from LiOH-mediated hydrolysis of 1E; 500 mg, 1.44 mmol) and tert-butyl (Z)-N,N'-diisopropylcarbamimidate (867 mg, 4.33 mmol) in tert-butyl alcohol ( 1 ml)/THF (1 ml) was stirred at room temperature for 18 hours. The reaction mixture was filtered; the filtrate was concentrated in vacuo. The crude oily product was purified by preparative HPLC (Sunfire C18, regenerated column 30x100 mm; detection at 220 nm; flow rate: 40 ml/min; continuous gradient from 20 to 100% B over 10 min + hold for 2 min at 100% B where A = 90:10 H ₂ O:MeCN and B = 90:10 MeCN:H ₂ O) to give the title compound (300 mg, 0.745 mmol, 51.6% yield) as a clear oil.

[M+H]+ = 403.2

137C. tert-Butyl (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane -1 -carboxylate

A mixture of 137B (300 mg, 0.75 mmol), DBU (0.23 ml, 1.49 mmol) and (PhO) ₂ PON ₃ (0.24 ml, 1.12 mmol) in THF (5 ml) was stirred at room temperature overnight. Ph ₃ P (391 mg, 1.49 mmol) and H ₂ O (1 ml) were added and the reaction mixture was stirred at room temperature for 2 h, then partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude oil was chromatographed (24 g SiO2; continuous gradient 0-10% EtOAc/hexane over 10 min) to give the title compound (280 mg, 0.697 mmol, 94% yield) as a clear oil.

[M+H]+ = 402.2.

Example 137.

The compound of example 137A (21 mg, 0.10 mmol) was added to a solution of the compound of example 137C (20 mg, 0.050 mmol) and iPr ₂ NEt (0.026 ml, 0.149 mmol) in DCM (1 ml) at 0°C for 5 minutes. The reaction mixture was stirred at room temperature for 20 h, after which TFA (0.5 ml) was added. The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The crude product was purified by preparative HPLC (regenerated Sunfire C18 30x100 mm column; detection at 220 nM; flow rate: 40 ml/min; continuous gradient from 30 to 100% B over 10 min + 2 min retention time at 100% B, where A = 90:10:0.1 H ₂ O:MeCN:TFA and B = 90:10:0.1 MeCN:H ₂ O:TFA) to give the title compound (TFA salt; 4 mg, 6. 0 µmol, 12% yield as a yellowish oil.

¹ H NMR (400 MHz, CDCl3) δ 8.00 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 4.77 (br d, J=1.3 Hz, 1H), 4.42 (s , 2Н), 4.15 (s, 3Н), 3.01 (d, J=7.7 Hz, 2Н), 2.93-2.82 (m, 1H), 2.75 (s, 3Н), 2.62 (s, 3Н), 2.15-1.49 ( m, 16H), 1.24-1.15 (m, 2H).

LCMS [M+H]+ = 521.3; hLPA1 IC ₅₀ = 167 nM.

Connections according to the following examples in the table. 6 was synthesized according to the procedures described for the compound of Example 136

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Table 6

Etc. No.

(lS,3S)-3-((6-(5-(((N-6yrnn-Nmethylsulfamoyl)amino)methyl)-1-methyl1 Η-1,2,3-triazol-4-yl)-2-methylpyridine -3 yl)oxy)cyclohexane-1-carboxylic acid

Analytical and biological data

LCMS, [M+H]+ = 495.2;

Ή NMR (500 MHz, CDC1 ₃ ) δ 8.03 (d, 7=8.8 Hz, 1H), 7.80 (br d, 7=8.8 Hz, 1H), 4.85 (brs, 1H), 4.48 (s, 2H), 4.18 (s, ZN), 3.15-3.08 (m, 2Н), 2.91 (brd, 7=3.9 Hz, 1Н), 2.78 (s, ZN), 2.73 (s, ZN), 2.20 - 1.64 (br, 9Н), 1.58 - 1.49 (m, 2Н), 1.32 (dq, 7=14.9, 7.4 Hz, 2Н), 0.93 (t, 7=7.3 Hz, ZN);

hLPAi IC50 = 449 nM.

(lS,3S)-3-((6-(5-(((N-6en ₃ nn-Nmethylsulfamoyl)amino)methyl)-1 -methyl1 Η-1,2,3-triazo l-4 -yl) - 2-methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid

LCMS, [M+H]+ = 529.2;

Ή NMR (400 MHz, CDC13) δ 7.99 (d, 7=8.8 Hz, 1H), 7.58 (br d, 7=8.6 Hz, 1H), 7.39 - 7.26 (m, 5H), 4.77 (br d, 7= 2.4 Hz, 1H), 4.45 (s, 2H), 4.25 (s, 2H), 4.11 (s, 3H), 2.87 (br s, 1H), 2.66 (s, 3H), 2.63 (s, 3H), 2.10 - 2.03 (m, 2H), 1.99 - 1.59 (br, 6H);

hLPAi 1С ₅₀ = 313nM.

Connections according to the following examples in the table. 7 was synthesized according to the procedures described for the compound of Example 64.

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Table 7

Etc. No. Structure and title Analytical and biological data 140 °Α γ ^ο ά ^Ν - \ ο (1 S,3 S) -3 - ((2-methyl-6- ( 1 -methyl-5 - (((pentan2-yloxy) carbonyl) amino) - 1H-1 ,2,3triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.2; Ή NMR (500 MHz, DMSO-de) δ 7.82 - 7.63 (m, 1H), 7.50 - 7.39 (m, 1H), 4.87-4.61 (m, 2H), 3.943.79 (m, 3H), 2.67 - 2.51 (m, 5H), 2.43 - 2.30 (m, 3H), 2.11 - 1.95 (m, 1H), 1.91 - 1.70 (m, 3H), 1.670.73 (m, 12H); hLPAi IC ₅₀ = 29 hM. 141 _ο <θγ° And ^he Αγο/, ^Ν Λ o Gu (1 S,3 S) -3 - ((6- (5 - (((cyclohexyloxy) carbonyl) amino) -1 -methyl- 1H-1,2, 3-triazol4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.2; Ή NMR (500 MHz, DMSO-de) δ 7.80 - 7.61 (m, 1H), 7.53 - 7.35 (m, 1H), 4.84 -4.66 (m, 1H), 4.61 4.44 (m, 1H), 3.96 - 3.76 ( m, 3H), 3.70 - 3.45 (m, 1H), 2.67 - 2.51 (m, 5H), 2.44 - 2.29 (m, 3H), 2.05 - 1.02 (m, 15H); hLPAi IC ₅₀ = 78 hM. 142 _ο ΰ _γ ° Am'm ^ν λ o c (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -(((pentan3-yloxy)carbonyl)amino)- 1H- 1,2,3triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.2; Ή NMR (500 MHz, DMSO-de) δ 7.80 - 7.63 (m, 1H), 7.54 - 7.42 (m, 1H), 4.93 - 4.70 (m, 1H), 4.61 4.45 (m, 1H), 3.94 - 3.76 ( m, 3H), 3.75 - 3.48 (m, 1H), 2.66 - 2.52 (m, 5H), 2.44-2.31 (m, 3H), 2.07 1.72 (m, 4H), 1.69 - 1.27 (m, 6H), 1.14 -0.51 (m, 5H); hLPAi IC ₅₀ = 30 hM.

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143 U ° ^Ν Λ o (1 S,3 S) -3 - ((6- (5 - (((2-fluoropropoxy) carbonyl) amino) -1 -methyl- 1H-1,2,3 -triazol4-yl) -2-methylpyridin-3-yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 436.1; Ή NMR (500 MHz, DMSO-de) δ 7.81 - 7.66 (m, 1H), 7.53 - 7.34 (m, 1H), 4.91 -4.70 (m, 2H), 4.34 4.04 (m, 2H), 3.93 - 3.83 ( m, 3H), 2.63 - 2.53 (m, 3H), 2.44 - 2.36 (m, 3H), 1.99 - 1.73 (m, 4H), 1.711.43 (m, 4H), 1.37 - 1.12 (m, 3H); hLPAi IC ₅₀ = 478 hM. 144 At Auo Ν-Ν\ Λ (1 S,3 S)-3 -((6-(5 -(((3-fluoropropoxy) carbonyl)amino)-1-methyl- 1H-1,2,3-triazol4-yl)-2-methylpyridin- 3-yl) hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 436.2; Ή NMR (500 MHz, DMSO-de) δ 7.81 - 7.65 (m, 1H), 7.48 - 7.34 (m, 1H), 4.85 -4.66 (m, 1H), 4.25 4.06 (m, 1H), 3.99 - 3.80 ( m, 3H), 3.63 - 3.36 (m, 3H), 2.68 - 2.53 (m, 4H), 2.43 - 2.33 (m, 3H), 2.06 1.39 (m, 9H); hLPAi IC ₅₀ = 254 hM. 145 Wu ” Wu-ψ F (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -(((3,3,3trifluoropropoxy)carbonyl)amino)-1H1,2,3-triazol-4-yl )pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 472.2; Ή NMR (500 MHz, DMSO-de) δ 7.84 - 7.66 (m, 1H), 7.52 - 7.37 (m, 1H), 4.86-4.71 (m, 1H), 4.42 4.06 (m, 2H), 3.93 - 3.79 ( m, 3H), 2.79–2.54 (m, 2H), 2.47–2.26 (m, 4H), 2.12–1.40 (m, 9H); hLPAi IC ₅₀ = 43 hM.

The compounds of the following examples were synthesized according to the procedures described above.

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Table 8

Etc. No. Structure and title Analytical and biological data Method 146 ₀ Λ _ν 0Η L ° Λγκ L Ν-Ν P \ ° / (lS,3S)-3-((6-(5-(3-((R)-lcyclopropylethyl)ureido)-1 -methyl1H-1, 2,3-triazol-4-yl)-2methylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt LC-MS, [M+H] ⁺ = 443.2; Ή NMR (500 MHz, DMSO-de) 8.37 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.20 (brd, 1=8.0Hz, 1H), 4.82-4.74 (m, 1H), 3.87 (s, 3H), 3.30-3.18 (m, 1H), 2.68 - 2.60 (m, 1H), 2.07 - 1.98 (m, 1H), 1.91 - 1.73 ( m, 3H), 1.70-1.44 (m, 4H), 1.16 (d, 1=6.9Hz, ZH), 0.940.82 (m, 1H), 0.46 - 0.33 (m, 2H), 0.33 - 0.25 (m, 1H), 0.21 0.11 (m, 1H). 26 out of 30 protons detected; the peak corresponding to methyl overlaps with the peak corresponding to DMSO-de; hLPAi 1C ₅₀ = 306 nM. Example 135 147 οΛΑοη Λ ° Λν ν-ν and __ \ O / (1 S,3 S)-3 -((2-methyl-6-(1-methyl-5 -(3 (pentan-2-yl)ureido)-1H-1,2,3triazol-4-yl)pyridine -3 yl)oxy)cyclohexane-1-carboxylic acid, TFA salt (mixture of diastereomers) LC-MS, [M+H]+ = 445.2; Ή NMR (500 MHz, CD ₃ CN) δ 8.01 (d, 7=8.8 Hz, 1H), 7.73 (br d, 7=8.8 Hz, 1H), 4.92 - 4.84 (m, 1H), 3.99 (s, 3H ), 3.92 -3.82 (m, 1H), 2.84 -2.76 (m, 1H), 2.60 (s, 3H), 2.16-2.07 (m, 1H), 1.951.86 (m, 3H), 1.82 - 1.35 (m , 8H), 1.20 (d, 7=6.6 Hz, SA), 0.95 (t, 7=7.3 Hz, SA). 29 out of 32 protons detected; hLPAi 1С ₅₀ =517nM. Example 135 148 at ⁰ and 1 I O Ν0 Η Ν (1 S,3 S) -3 - ((6- (5 - ((3 - (cyclobutyl methyl) -3-methylureido) methyl) -1 methyl- 1H-1,2 ,3-triazol-4-yl)-2ethylpyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ = 485.2; Ή NMR (500 MHz, DMSO-de) δ 7.88 (d, 7=8.6 Hz, 1H), 7.557.47 (m, 1H), 6.56 - 6.35 (m, 1H), 4.78 (br s, 1H), 4.69 (br d, 7=5.4 Hz, 2H), 4.10 (s, 3H), 2.94 (br s, 1H), 2.87 (q, 7=7.5 Hz, 2H), 2.73 (s, 3H), 2.65 (brt, 7=10.4 Hz, 1H), 2.47 - 2.27 (m, 2H), 2.04 (brd,7=14.1 Hz, 1H), 1.90 - 1.79 (m, 5H), 1.78 - 1.71 (m, 2H), 1.69 - 1.54 (m, 6H), 1.35 - 1.26 (m, 3H); hLPAi IC ₅₀ = 62 nM. Example 108

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149 o II j I o /c ⁿ /pf (18.38)-3-((6-(5-((3-benzyl-3methylureido)methyl)-1-methyl- 1H1,2,3-triazole-4- yl)-2-ethylpyridin3-yl)oxy)cyclohexane-1 carboxylic acid 150 ^ΑΑ,/ΟΗ 9 o and 1 I O VC _N X /k Ν-Ν^ Η (18.38)-3-((6-(5-((3-butyl-3methylureido)methyl)-1-methyl - 1H1,2,3-triazol-4-yl)-2-ethyl-pyridin3-yl)oxy)cyclohexane-1 carboxylic acid 151 ___J , JDH /хт ⁰ n η I 0 NN\ HN 4-yl)-2-ethylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid 152 D„ / OH ⁰ n η I O Ν-Ν Η Ν \ \ ^Η \Ζ (1 S,3 S) -3 - ((6- (5 - ((3 - (cyclopropyl methyl) ureido) methyl) -1 -methyl-1H-1,2,3-triazol-4-yl)-2-ethyl-pyridin3-yl)oxy)cyclohexane-1 carboxylic acid 153 ^DD.OH γ /xt o n 1 T o ^Ν -\ ⁿ ηΎχ (18.38) -3- ((6- (5- ((3-benzylureido) methyl) -1 -methyl- 1H-1 ,2,3 triazol-4-yl)-2-ethylpyridin-3 yl)oxy)cyclohexane-1-carboxylic acid

LC-MS, [M+H] ⁺ = 507.4; Ή NMR (500 MHz, DMSO-de) δ 8.01-7.78 (m, 7=8.5 Hz, 1H), 7.55 -7.37 (m, 7=8.6 Hz, 1H), 7.28 -7.22 (m, 2H), 7.22 - 7.15 (m, 1H), 7.09 (br d, 7=7.3 Hz, 2H), 6.62 (br s, 1H), 4.75 (br d, 7=5.5 Hz, ZH), 4.40 (s, 2H), 4.10 ( s, 3H), 2.83 - 2.68 (m, 5H), 2.63 (brs, 1H), 2.14-1.96 (m, 1H), 1.92 (s, 2H), 1.84 (brd,7=13.8 Hz, ZN), 1.65 (br s, 2H), 1.56 (br d, 7=19.5 Hz, 2H), 1.28 - 1.19 (m, 3H); hLPAi IC ₅₀ = 143 nM Example 108 LC-MS, [M+H] ⁺ = 473.5; Ή NMR (500 MHz, DMSO-de) δ 7.93 - 7.80 (m, 1H), 7.59 - 7.45 (m, 1H), 6.58 - 6.39 (m, 1H), 4.85 -4.73 (m, 1H), 4.65 (brd , 7=4.9 Hz, 2H), 4.08 (s, 3H), 3.09 (brt, 7=7.3 Hz, 2H), 2.85 (q, 7=7.3 Hz, 2H), 2.71 (s, 3H), 2.66 -2.57 (m, 1H), 2.10- 1.95 (m, 1H), 1.88 - 1.75 (m, 3H), 1.71 1.54 (m, 3H), 1.54- 1.42 (m, 1H), 1.26 (brt, 7=7.5 Hz, 5H), 1.14-1.06 (m, 2H), 0.76 (t, 7=7.3 Hz, ZN); hLPAi IC ₅₀ = 44 nM Example 108 LC-MS, [M+H] ⁺ = 459.3; Ή NMR (500 MHz, DMSO-de) δ 7.85 (d, 7=8.5 Hz, 1H), 7.50 (d, 7=8.5 Hz, 1H), 6.29 - 6.20 (m, 1H), 6.16-6.13 (m, 1H), 4.76 (brs, 1H), 4.68 (brd, 7=5.8 Hz, 2H), 4.10(s, 3H), 2.93 (q, 7=6.4 Hz, 2H), 2.86 (q, 7=7.6 Hz, 2H), 2.03 - 1.88 (m, 1H), 1.83 - 1.76 (m, 3H), 1.63 (brd,7=9.5 Hz, 2H), 1.53 (brd,7=12.2 Hz, 2H), 1.30- 1.17 (m , 9H), 0.81 (t, 7=7.2 Hz, ZN); hLPAi IC ₅ o = 647 nM. Example 108 LC-MS, [M+H] ⁺ =471.4; Ή NMR (500 MHz, DMSO-de) δ 7.84 (d, 7=8.5 Hz, 1H), 7.61 (br d,7=8.5 Hz, 1H), 6.62 (brt, 7=5.6 Hz, 1H), 4.72 - 4.62 (m, 3H), 4.08 (s, 3H), 3.02 (d,7=6.7 Hz, 2H), 2.87-2.80 (m, 2H), 2.80 -2.73 (m, 3H), 1.94 (brs, 1H) , 1.67 (brs, 3H), 1.63 - 1.54 (m, 3H), 1.50 (br s, 1H), 1.26 (t, 7=7.6 Hz, ZN), 0.78 (br d, 7=6.4 Hz, 1H), 0.33 (br d, 7=7.6 Hz, 2H), 0.10 (br d, 7=4.6 Hz, 2H); hLPAi IC ₅₀ = 270 nM. Example 108 LCMS, [M+H]+ = 493.3; Ή NMR (500 MHz, DMSO-de) δ 7.89 (d, 7=8.5 Hz, 1H), 7.52 (d, 7=8.5 Hz, 1H), 7.33 -7.17 (m, 5H), 4.80 (brs, 1H) , 4.74 (s, 2H), 4.19 (br d, 7=5.2 Hz, 2H), 4.13 (s, 3H), 2.88 (q, 7=7.3 Hz, 2H), 2.63 (brt, 7=10.5 Hz, 1H ), 2.04 (br d, 7=13.4 Hz, 1H), 1.88 (brd, 7=11.9 Hz, 1H), 1.851.74 (m, 2H), 1.68 - 1.48 (m, 4H), 1.35 - 1.23 (m , 3H); hLPAi IC ₅₀ = 107 nM. Example 108

Intermediate 8. 4-Nitrophenyl (4-oxopentyl) carbonate

Pyridine (0.95 ml, 11 8 mmol). The reaction mixture was stirred at room temperature for 48 hours; the solids were filtered off and the filtrate was concentrated in vacuo to give the crude product. This product was chromatographed (40 g SiO ₂ ; continuous gradient from 0 to 50% EtOAc in hexanes over 12 minutes, then held at 50% EtOAc in hexanes over 10 minutes) to give the title compound (500 mg,

1.871 mmol, 47.8% yield as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34-8.21 (m, 2H), 7.40-7.33 (m, 2H), 4.31 (t, J=6.3 Hz, 2H), 2.62 (t, J=7.0 Hz, 2Н), 2.19 (s, 3H), 2.10-1.96 (m, 2H).

LC-MS [M+H]+ = 268.1.

The 4-nitrophenyl carbonate intermediates needed to prepare the compounds of the following examples were synthesized from the corresponding alcohols according to the procedure described for the preparation of intermediate 2.

Intermediate connection no. Structure and name Analytical data 9 ° ^2N ^-\ 1/1 o F 4-nitrophenyl (4,4,4-trifluoro-2methylbutyl) carbonate Ή NMR (400 MHz, CDC1 ₃ ) δ 8.32 - 8.24 (m, 2H), 7.42 - 7.34 (m, 2H), 4.29 - 4.14 (m, 2H), 2.45 - 2.26 (m, 2H), 2.17-1.99 ( m, 1Н), 1.17 (d, 7=6.2 Hz, ZN). 10 Ua π 3,3-difluorobutyl(4-nitrophenyl)carbonate LCMS, [M + Η] ⁺ = 276.0; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.29 (d,7= 9.1 Hz, 2H), 7.38 (d,7= 9.0 Hz, 2H), 4.50 (t, 7= 6.6 Hz, 2H), 2.36 (tt, 7= 15.6, 6.6 Hz, 2H), 1.70 (t, 7= 18.6 Hz, ZN). eleven Ο ₂ N^ III ⁰ Λ 4-nitrophenyl-spiro[2.3]hexan-5-yl carbonate LCMS, [M + H] ⁺ = 264.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.28 (dd, 7= 9.0, 1.7 Hz, 2H), 7.40 (d, 7= 9.2 Hz, 2H), 5.29 (p, 7 = 7.0 Hz, 1H), 2.60 - 2.49 (m, 2Н), 2.49 2.35 (br, 2Н), 0.52 (br s, 4Н). 12 Ο ₂ Ν^~ O ⁰ "F YA A LA 3,3-difluorocyclobutyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 274.0; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.31 (d,7= 9.1 Hz, 2H), 7.41 (d,7= 9.2 Hz, 2H), 5.07 (qtd, 7= 7.6, 5.5, 3.4 Hz, 1H), 3.15 (ddt,7= 15.6, 11.5, 7.1 Hz, 2H), 2.96 - 2.78 (m, 2H). 13 BH ₀ А F (2,2-difluorocyclopropyl)methyl(4nitrophenyl)carbonate LCMS, [M + H] ⁺ = 274.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.32 (d, 7= 9.2 Hz, 2H), 7.43 (d, 7= 9.3 Hz, 2H), 4.46 - 4.29 (br, 2H), 2.17 - 2.08 (m, 1H ), 1.66 (tdd, 7 = 11.5, 8.1, 4.8 Hz, 1H), 1.37 (dtd, 7 = 13.2, 7.7, 3.9 Hz, 1H). 14 O ₂ N ^_ III O F 2,2-difluoropropyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 262.0; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.33 (d,7= 9.1 Hz, 2H), 7.44 (d,7=9.2 Hz, 2H), 4.45 (t,7= 11.8 Hz, 2H), 1.78 (t, 7= 18.6 Hz, ZN).

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15 O ₂ N ^_ Yadch F 4-nitrophenyl (2,2,3,3,3 pentafluoropropyl) carbonate LCMS, [M + H] ⁺ = 316.6; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.34 (d, J= 9.2 Hz, 2H), 7.44 (d, J= 9.2 Hz, 2H), 4.76 (td, J= 12.4, 1.1 Hz, 2H). 16 O ₂ N^ ill about F 4,4-difluoro-2-methylbutyl (4nitrophenyl) carbonate LCMS, [M + H] ⁺ = 290.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.32 (d, J= 92 Hz, 2H), 7.42 (d, J= 92 Hz, 2H), 5.99 (tt, J= 56.4, 4.6 Hz, 1H), 4.22 ( qd, J= 10.7,6.1 Hz, 2H), 2.29 (dq, J= 13.2, 6.6 Hz, 1H), 2.15 2.00 (m, 1H), 1.93 - 1.78 (m, 1H), 1.16 (d, J= 6.8 Hz, 3H) 17 O ₂ N^ k W ° Chdm 2-(1-methylcyclopropyl)ethyl(4nitrophenyl)carbonate LCMS, [M + H] ⁺ = 266.1; 'HNMR (400 MHz, CDC1 ₃ ) δ 8.28 (d, J= 9.2 Hz, 2H), 7.38 (d, J= 92 Hz, 2H), 4.41 (t,7 = 7.1 Hz, 2H), 1.70 (t, J= 7.1 Hz, 2H), 1.10 (s, 3H), 0.43 - 0.27 (m, 4H). 18 III o NA _o y 2-cyclopropylpropyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 266.1; 'HNMR (500 MHz, CDC1 ₃ ) δ 8.31 (d, J= 9.1 Hz, 2H), 7.43 - 7.38 (m, 2H), 4.37 (dd, J= 10.4, 5.5 Hz, 1H), 4.19 (dd, J = 10.4, 7.0 Hz, 1H), 1.25-1.15 (m, 1H), 1.12 (d, J= 6.6 Hz, 3H), 0.63 (ddt, J= 13.6, 9.1, 4.3 Hz, 1H), 0.57 - 0.45 ( m, 2H), 0.25 (ddd, J= 10.2, 4.5, 1.8 Hz, 1H), 0.15 (ddd, J= 9.2, 4.8, 1.4 Hz, 1H). 19 O ₂ N._ III o Chlm 2-cyclopropylethyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 252.1 Ή NMR (500 MHz, CDC1 ₃ ) δ 8.31 (d, J= 9.1 Hz, 2H), 7.41 (d, J= 9.1 Hz, 2H), 4.39 (t, J= 6.7 Hz, 2H), 1.69 (q, J= 6.8 Hz, 2H), 0.88 - 0.73 (m, 1H), 0.62 - 0.47 (m, 2H), 0.16 (dt, J= 6.0, 4.5 Hz, 2H ). 20 °M 0 LA a 3-fluorobenzyl(4-nitrophenyl)carbonate Ή NMR (500 MHz, CDC1 ₃ ) δ 8.24 - 8.17 (m, 2H), 7.37 - 7.27 (m, 3H), 7.14 (d, 3=1.1 Hz, 1H), 7.09 (dt, 7=9.2, 1.9 Hz , 1H), 7.02 (td, 7=8.4, 1.9 Hz, 1H), 5.22 (s, 2H). 21 ° ^2N Y ^ 0 And a (S) -2 -methylbutyl (4 -nitrophenyl) carbonate LCMS, [M + Na] ⁺ = 276.0; 'H NMR (500 MHz, CDC1 ₃ ) δ 8.30 (d, 7= 9.1 Hz, 2H), 7.41 (d, 7=9.2 Hz, 2H), 4.21 (dd, J= 10.4, 6.0 Hz, 1H), 4.12 (dd, J= 10.4, 6.8 Hz, 1H), 1.87 (dddd, J= 12.4, 7.9, 6.8, 5.8 Hz, 1H), 1.53 (dtd, J= 15.0, 7.5, 5.6 Hz, 1H), 1.36-1.23 (m, 1H), 1.03 (d, J= 6.7 Hz, 3H), 0.98 (t, 7=7.5 Hz, 3H).

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22 O UL A 4-fluorobutyl(4-nitrophenyl)carbonate LCMS, [M + Na] ⁺ = 280.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.29 (d, J= 92 Hz, 2H), 7.40 (d,7=9.1 Hz, 2H), 4.58 (t,7=5.5 Hz, 1H), 4.49 (t, 7= 5.7 Hz, 1H), 4.37 (t, 7 = 6.2 Hz, 2H), 2.00 - 1.79 (m, 4H). 23 °m o L 1 A ^ _Z .^F (1 - (2-fluoroethyl) cyclopropyl) methyl (4 nitrophenyl) carbonate LCMS, [M + Na] ⁺ = 306.3; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.31 (d,7= 9.2 Hz, 2H), 7.42 (d,7= 9.2 Hz, 2H), 4.69 (t,7= 5.9 Hz, 1H), 4.60 (t, 7= 6.0 Hz, 1H), 4.20 (s, 2H), 1.91 (t, 7= 6.0 Hz, 1H), 1.86 (t, 7= 6.0 Hz, 1H), 0.73 - 0.56 (m, 4H). 24 ° ^2N A 0 c / L 1 x U mAoAl (2,2-dimethylcyclopropyl)methyl(4nitrophenyl)carbonate LCMS, [M + Na] ⁺ = 287.9; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.10 (d,7= 9.1 Hz, 2H), 7.21 (d,7=9.1 Hz, 2H), 4.25 (dd,7= 11.5, 7.0 Hz, 1H), 3.98 ( dd, 7= 11.5, 8.9 Hz, 1Н), 1.61-1.53 (m, 1Н), 1.33 - 1.23 (br, 1Н), 0.97 (s, ZN), 0.94 (s, ZN), 0.88 (tdd, 7 = 8.8, 6.9, 5.3 Hz, 1H). 25 0 I L I A A (8)-4-nitrophenyl-pentan-2-yl-carbonate LCMS, [M + Na] ⁺ = 276.0; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.30 (d, 7= 9.2 Hz, 2H), 7.41 (d,7=9.1 Hz, 2H), 5.00 -4.85 (br, 1H), 1.77 (dddd, 7= 13.0 , 9.9, 7.2, 5.5 Hz, 1Н), 1.66 - 1.58 (m, 1Н), 1.53 - 1.42 (br, 2Н), 1.40 (d, 7= 6.3 Hz, ZN), 0.99 (t, 7 = ZN). 26 ^θ2Ν N^ o F _p LI i A 4-nitrophenyl(5,5,5-trifluoropentyl)carbonate Ή NMR (500 MHz, CDC1 ₃ ) δ 8.31 (d, 7 = 9.1 Hz, 2H), 7.41 (d, 7 = 9.2 Hz, 2H), 4.35 (t, 7 = 6.3 Hz, 2H), 2.25 - 2.13 ( m, 2Н), 1.88 (dt, 7= 9.0, 6.4 Hz, 2Н), 1.77 (tt, 7 = 10.6.6.1 Hz, 2Н). 27 ^θ2Ν Α 0 = L 1 1 a LCMS, [M + H] ⁺ = 252.0; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.30 (d, 7= 9.2 Hz, 2H), 7.41 (d, 7= 9.2 Hz, 2H), 4.32 (dq, 7= 8.8, 6.3 Hz, 1H), 1.49 ( d,7= 6.3 Hz, ZN), 1.22 - 1.10 (m, 1H), 0.72 - 0.61 (m, 2H), 0.61 0.51 (m, 1H), 0.41 - 0.28 (m, 1H). 28 ^θ2Ν Α 0 = L 1 AA (R)-4-niΊpoφenyl-pentan-2-yl-κapbonate LCMS, [M + Na] ⁺ = 276.0; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.30 (d,7= 9.1 Hz, 2H), 7.41 (d,7=9.2 Hz, 2H), 4.93 (dt,7=7.3, 6.0 Hz, 1H), 1.82- 1.71 (m, 1H), 1.62 (ddt, 7= 13.8, 9.6, 5.9 Hz, 1H), 1.54 - 1.42 (br, 2H), 1.40 (d, 7= 6.3 Hz, ZN), 0.99 (t, 7 = 7.3 Hz, ZN). 29 ° ^2N A 0 L 1 1 x L (trans-2-methylcyclopropyl)methyl(4nitrophenyl)carbonate LCMS, [M + H] ⁺ = 252.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.31 (d,7= 9.1 Hz, 2H), 7.42 (d,7=9.1 Hz, 2H), 4.15 (qd,7= 11.2, 7.5 Hz, 2H), 1.12 ( d, 7= 6.0 Hz, ZN), 1.00 (tq, 7= 7.7, 4.5, 3.9 Hz, 1H), 0.87 - 0.78 (m, 1H), 0.57 (dt, 7= 9.0, 4.8 Hz, 1H), 0.45 (dt,7= 8.1, 5.1 Hz, 1H).

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thirty ABOUT L A a (3,3-d ifluorocyclobutyl)methyl(4nitrophenyl)carbonate LCMS, [M + H] ⁺ = 288.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.37 - 8.23 (m, 2H), 7.48 7.36 (br, 2H), 4.38 (d, J= 6.7 Hz, 2H), 2.87 -2.72(br, 2H), 2.64 ( dddd,7 = 13.1, 10.8, 8.7, 5.3, 3.3 Hz, 1H), 2.57 - 2.40 (m, 2H). 31 ° ^2N ΊΑ o ί p L 1 a j< ^F 4-nitrophenyl (3,3,3-1 fluoropropyl) carbonate LCMS, [M + Na] ⁺ = 280.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.32 (d, J= 9.2 Hz, 2H), 7.42 (d, J= 9.2 Hz, 2H), 4.55 (t, J= 6.3 Hz, 2H), 2.65 (qt, J= 10.2, 6.3 Hz, 2H). 32 ° ^2N ^ o L 1 a / (2-methylcyclopropyl) methyl (4 nitrophenyl) carbonate LCMS, [M + H] ⁺ = 252.1; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.31 (d, J= 9.1 Hz, 2H), 7.42 (d,7=9.1 Hz, 2H), 4.15 (qd, J= 11.2, 7.5 Hz, 2H), 1.12 ( d, J= 6.0 Hz, ZN), 0.99 (tq, J= 7.9, 4.4, 3.9 Hz, 1H), 0.93 - 0.78 (m, 1H), 0.57 (dt, J= 9.1, 4.8 Hz, 1H), 0.45 (dt,7= 8.2, 5.1 Hz, 1H). 33 ° ^2N ΥΥ o . L 1 A 1 (8) -1-cyclopropylethyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 252.0; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.38 - 8.19 (m, 2H), 7.47 7.37 (m, 2H), 4.32 (dq, J= 8.9, 6.4 Hz, 1H), 1.49 (d,7=6.3 Hz, ZN), 1.16 (qt, 7 = 8.5, 4.9 Hz, 1H), 0.71 - 0.61 (m, 2H), 0.60 -0.53 (m, 1H), 0.35 (ddd, 7= 10.2.5.0.3.8 Hz, 1H) . 34 ° ^2Ν ύΛ o I L 1 a JU (8)-sec-butyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 240.0; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.30 (d,7= 9.1 Hz, 2H), 7.41 (d,7=9.2 Hz, 2H), 4.87 (h, 7= 6.3 Hz, 1H), 1.85 - 1.65 ( w, 2Н), 1.40 (d, 7= 6.2 Hz, ZN), 1.02 (t, 7= 7.5 Hz, ZN). 35 L 1 A A / (K)-sec-butyl (4-nitrophenyl) carbonate LCMS, [M + Na] ⁺ = 262.1; Ή NMR (500 MHz, CDCI3) δ 8.30 (d,7= 9.1 Hz, 2H), 7.41 (d,7=9.2 Hz, 2H), 4.86 (p, 7= 6.3 Hz, 1H), 1.85 - 1.63 (w , 2Н), 1.40 (d, 7= 6.3 Hz, ZN), 1.02 (t, 7= 7.4 Hz, ZN). 36 ° ^2Ν ΥΊ o 1 II II and 1 / (8)-3-methylbutan-2-yl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 254.1; Ή NMR (500 MHz, CDCI3) δ 8.30 (d,7= 9.2 Hz, 2H), 7.41 (d,7=9.1 Hz, 2H), 4.75 (p,7=6.2 Hz, 1H), 2.02 - 1.90 (br , 1H), 1.36 (d, 7= 6.3 Hz, 3H), 1.02 (dd, 7= 6.9, 3.0 Hz, 6H). 37 ^θ2Ν ΎΧ o \u003d 1' II 11L / (K) -3-methylbutan-2-yl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 254.1; Ή NMR (500 MHz, CDCI3) δ 8.30 (d,7= 9.2 Hz, 2H), 7.41 (d,7=9.1 Hz, 2H), 4.75 (p,7=6.2 Hz, 1H), 2.02 - 1.90 (br , 1H), 1.36 (d, 7= 6.3 Hz, 3H), 1.02 (dd, 7= 6.9, 3.0 Hz, 6H). 38 o r LA a F 4-ni1rophenyl-(4,4,4-1rifluorobutyl)carbonate LCMS, [M + H] ⁺ = 294; Ή NMR (400 MHz, CDCI3) δ 8.32 (d,7= 9.2 Hz, 2H), 7.41 (d,7= 9.2 Hz, 2H), 4.39 (t, 7= 6.3 Hz, 2H), 2.38 - 2.23 (m , 2H), 2.14–2.01 (w, 2H). 39 O ₂ N^^. / /) О I oAjY 3,3-dimethylcyclobutyl (4-nitrophenyl) carbonate LCMS, [M + H] ⁺ = 266; Ή NMR (500 MHz, CDCI3) δ 8.20 (d,7= 9.1 Hz, 2H), 7.30 (d,7= 9.2 Hz, 1H), 5.01 (p,7=7.3 Hz, 1H), 2.28 - 2.22 (m , 2H), 1.96 (ddd, 7 = 10.1, 7.2, 2.9 Hz, 2H), 1.13 (s, 3H), 1.09 (s, 3H).

The compounds of the examples in the following table were synthesized according to the procedures described for the preparation of the compounds of examples 1 and 2 using the above 4-nitrophenyl carbonate intermediates.

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Etc. No. Structure and name Analytical and biological data Method 154 οΌγΟΗ A ° Νχ-Ν X ⁰ Ν-Ν Η ^υ )^\< ^{F 4 1} X ^F (1 S,3 S)-3-((2-( 1 -methyl-5 -((((4,4 ,4trifluoro-2-methylbutoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 501.4; Ή NMR (500 MHz, DMSOd^ δ 8.64 (s, 2H), 7.59 (s, lH), 4.88(s, 1H), 4.75 (d,7= 5.5 Hz, 2H), 4.08 (s, 3H), 3.83 (d,7=6.1 Hz, 2H), 2.72-2.63 (m, 1H), 2.37-1.48 (m, JH), 0.94 (d, J= 6.6 Hz, ZH), hLPAi IC ₅₀ = 2905 hM. Example 1 155 οΌγΟΗ N^y^ o ΑγΝ X ° c Ν-Ν H ° f \ < ^{F 4} / _f Af (1 S,3 S) -3 - ((3 -methyl-5 - (1 -methyl-5 ((( (4,4,4-trifluoro-2-methylbutoxy)carbonyl)amino)methyl)- 1H-1,2,3triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 515.3; Ή NMR (500 MHz, DMSOdl) δ 8.59 (s, 1H), 7.60 (s, 1H), 5.38 (s, 1H), 4.72 (d,J= 5.3 Hz, 2H), 4.05 (s, 3H), 3.82 (d, 7= 6.2 Hz, 2H). 2.69 -2.58 (m, 1H), 2.33-1.41 (m, 10H), 0.93 (d, 7= 6.6 Hz, ZN); hLPAi IC ₅₀ = 85 hM. Example 1

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156 οΌ'γΟΗ V o Ά ^ν Τ 0 ^ν αΆνΧ^__ ν-ν η ^υ γη (1 S,3 S)-3 -((5 -(5 -((((cyclobutyl methoxy)carbonyl)amino)methyl)- 1 methyl-1H-1,2,3-triazol-4-yl)-3 methylpyrazin-2-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 459.3; Ή NMR (500 MHz, DMSOU) δ 8.55 (s, 1H), 7.55 (s, 1H), 5.39 (brs, 1H), 4.71 (d, J= 5.5 Hz, 2H), 4.07 (s, 3H), 3.91 (d, 7= 6.8 Hz, 2H), 2.69 - 2.59 (m, 1H), 2.47 (s, 3H), 2.14-1.42 (m, 15H); hLPAi IC ₅₀ =213hM. Example 1 157 Ο^Ο'γΟΗ Chi ⁰ X ⁰ ν-ν Η ^ϋ (1 S,3 S)-3 -((6-(5 -((((2-cyclopropylethoxy)carbonyl)amino)methyl)-1 methyl- 1H -1,2,3-triazol-4-yl)-2methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.2; Ή NMR (500 MHz, DMSO7 ₆ )δ7.82 (d, 7= 8.6 Hz, 1H), 7.50 (brs, 1H), 7.47 (d,7 = 8.6 Hz, 1H), 4.82-4.65 (m, 3H) , 4.04 (s, 3H), 3.98 (br s, 2H), 2.66–2.57 (m, 1H), 2.43 (s, 3H), 2.04–1.08 (m, 10H), 0.64 (brs, 1H), 0.33 ( brs, 2H), 0.0 (brs, 2H); hLPAi IC ₅₀ = 19 nM. Example 1 158 γ Chi ⁰ X ⁰ ν ΑΓ^ν Jr ν-ν η ^υ (1 S,3 S)-3 -((5 -(5 -((((3,3-dimethylbutoxy)carbonyl)amino)methyl)-1 methyl-1H-1,2,3-triazol-4-yl)-3 methylpyrazin-2-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 475.4; Ή NMR (500 MHz, DMSOde) δ 8.54 (s, 1H), 7.47 (s, 1H), 5.38 (brs, 1H), 4.69 (br s, 2H), 4.05 (s, 3H), 4.0 3.88 (m, 2H), 2.67-2.57 (m, 1H), 2.46 (s, 3H), 2.12-1.37 (m, 10H), 0.85 (s, 9H); hLPAi IC ₅₀ = 76 hM. Example 1

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159 ο^ΟγΟΗ ⁰ C/N Τ 0 nn^ η ⁰ (1 S,3 S) -3 - ((5 - (5 - ((((3-fluorobenzyl) oxy) carbonyl) amino) methyl) -1 - methyl1 Η-1,2,3-triazol-4-yl)-3 methylpyrazin-2-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 498.9; Ή NMR (500 MHz, DMSOde) δ 8.55 (s, 1H), 7.74 (s, 1H), 7.38 (d, J= 7.3 Hz, 1H), 7.12 (t, J= 10.3 Hz, 2H), 5.37 (s , 1H), 5.02 (s, 2H), 4.794.63 (m, 2H), 4.06 (s, 3H), 2.60 - 2.55 (m, 1H), 2.44 (s, 3H), 2.10 - 1.36 (m, 8H ); hLPAi IC ₅₀ = 122 nM. Example 1 160 Ο-ΟγΟΗ ° C/N T o VO n-n n ° (1 S,3 S)-3 -((5 -(5 -((((2-cyclopropyl ethoxy)carbonyl)amino)methyl)-1 methyl- 1H-1,2,3-triazol-4-yl) -3 methylpyrazin-2-yl)oxy)cyclohexane1-carboxylic acid LCMS, [M + H] ⁺ = 459.0; Ή NMR (500 MHz, DMSOD) δ 8.54 (s, 1H), 7.50 (s, 1H), 5.38 (s, 1H), 4.70 (d,J= 5.5 Hz, 2H), 4.06 (s, 3H), 3.97 (t, J= 6.7 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.46 (s, 3H), 2.11-1.32 (m, 10H), 0.64 (s, 1H), 0.34 (d, 7= 7.9 Hz, 2H), 0.00 (d, J= 4.9 Hz, 2H); hLPAi IC ₅₀ = 66 nM. Example 1 161 x9'Y ^0H γ |C ⁰ T O νΧ ν N-ν η £ X (1 S,3 S)-3 -((3-methyl-5 -(1-methyl-5 (((((8)- 2-methylbutoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyrazin-2-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 460.9; Ή NMR (500 MHz, DMSOd ₆ ) δ 8.54 (s, 1H), 7.51 (s, 1H), 5.38 (s, 1H), 4.7O (s, 2H), 4.06 (s, 3H), 3.80-3.67 ( m, 2H), 2.61-2.56 (m, 1H), 2.46 (s, 3H), 2.10-1.24 (m, 10H), 1.11-1.01 (m, 1H), 0.84-0.75 (m, 6H); hLPAi IC ₅₀ = 109 nM. Example 1

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162 ΛγΟΗ [Ύ^ ° Τ 0 Ν-Ν\ η °^^s/F (18.38)-3-((6-(5-((((4-fluorobutoxy)carbonyl)amino)methyl)-1-methyl-1H1,2,3-triazo l-4-yl)-2- methyl-pyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 464.1; Ή NMR (500 MHz, DMSOU) δ 7.84 (d, J= 8.5 Hz, 1H), 7.48 (d, 7= 8.6 Hz, 1H), 4.76 (d, 7= 5.7 Hz, 3H), 4.47(t.7 = 6.0 Hz, 1H), 4.37 (d, 7= 6.4 Hz, 1H), 4.06 (s, 3H), 3.99 (t, 7= 6.0 Hz, 2H), 2.70-2.61 (m, 1H), 2.46 (s , 3H), 2.07 1.44 (m, 12H); hLPAi IC ₅₀ = 60 hM. Example 1 163 Lt ^he ° U / N X ° NN H ° (lS,3S) -3- ((6- (5- (((((1- (2-fluoroethyl) cyclopropyl) methoxy) carbonyl) amino) methyl) -1 - methyl- 1H-1,2,3triazo l-4 -yl) -2-methylpyridin-3 -yl) hydroxy) cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 490.1; Ή NMR (500 MHz, DMSOU) δ 7.58 (d, 7= 8.5 Hz, 1H), 7.27 (d, 7= 8.7 Hz, 1H), 4.51 (d, 7= 5.6 Hz, 3H), 4.29(t.7 = 6.4 Hz, lH), 4.20(t,7=6.4 Hz, 1Н), 3.81 (s, ZN), 3.59 (sn 2H), 2.20 (s, ZN), 1.791.21 (m, YuN), 0.21- 0.04 (m, 4H). (Proton a to acid is not observed due to water suppression); hLPAi 1C ₅₀ = 88 nM. Example 1 164 Ο^Ο-γΟΗ ⁰ X ⁰ N^N nn Η ° (IS, 38)-3-((6-(5-(((((2,2-dimethylcyclopropyl)methoxy)carbonyl)amino)methyl)-1 -methyl- 1H-1,2,3triazo l-4 -yl) -2 -methylpyride in-3 -yl) hydroxy) cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 472.1; Ή NMR (500 MHz, DMSO7b) δ 7.68 (d, 7= 8.5 Hz, 1H), 7.32 (D7=8.6 Hz, 1H), 4.59 (d, 7= 5.7 Hz, 3H), 3.91 (s, 4H), 3.67 (dd, 7= 11.6, 8.6 Hz, 1H), 2.55 - 2.46 (m, 1H), 2.31 (s, 3H), 1.92-1.29 (br, 8H), 0.86 (s, 3H), 0.84 (s, ZN), 0.69 (d,7= 14.2 Hz, 1H), 0.29 (dd, 7= 8.6, 4.3 Hz, 1H); hLPAi 1C ₅₀ = 65 nM. Example 1

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165 Ο<θ-γ°Η ySy ° Τ ο Ν-Ν _χ Η ^υ (1 S,3 S)-3 -((2-methyl-6-( 1 -methyl-5 ((((((S) - pentan-2-yl)oxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 460.1; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.82 (d, 7= 8.5 Hz, 1H), 7.52 - 7.44 (m, 2H), 4.74 (br s, 3H), 4.65 (s, 1H), 4.04 (s, 3H), 2.44 (s, 3H), 2.00-1.30 (m, 10H), 1.28-1.18 (m, 2H), 1.11 (d, 7=6.1 Hz, ZN), 0.84 (t, 7= 7.4 Hz, ZN ). (Proton a to acid is not observed due to water suppression); hLPAi 1C ₅₀ = 34 nM. Example 1 166 At ° ⁿ mH ⁰ t ° G F Ν-Ν _χ N ^m (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 (((((5.5.5 - trifluoropentyl)oxy)carbonyl)amino)methyl)-1H-1,2,3triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 514.1; Ή NMR (500 MHz, DMSOT) δ 7.82 (d, 7= 8.5 Hz, 1H), 7.58 (s, 1H), 7.53 (d, 7=8.6 Hz, 1H), 4.76 (d, 7= 5.4 Hz, 2H ), 4.71 (s, 1H), 4.05 (s, ZH), 3.97 (t,7= 6.5 Hz, 2H), 2.24 (brs, 2H), 1.97-1.40 (m, JH). (Protons a to carboxylic acid and -CH3 are not observed on pyridine due to water suppression); hLPAi 1C ₅₀ = 121 nM. Example 1 167 ^Atom [K ° D / N X ° cAgxAm Ν-Ν H ° V-7 (18.38) -3- ((6- (5- (((((K) -1-cyclopropylethoxy) carbonyl) amino) methyl )-1-methyl-1 Η-1,2,3-triazo l-4 yl)-2-methylpyridin-3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 457.9; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.63 (d, 7= 8.5 Hz, 1H), 7.29 (p7=8.6Hz, 1H), 4.58 (s, 1H), 4.54 (s, 2H), 3.953.89 ( m, 1H), 3.84 (s, 3H), 2.46-2.38 (m, 1H), 1.86 1.23 (m, 8H), 1.01-0.92 (m, 3H), 0.76 - 0.67 (m, 1H), 0.27- - 0.03 (m.74H). (-CH ₃ on pyridine are not observed due to water suppression); hLPAi 1C ₅₀ = 427 nM. Example 1

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168 LL (Λ ° Τ O ^ν 9τ^ν ν-ν Η ^υ (1 S,3 S) -3 - ((6- (5 - ((((3,3-dimethylcyclobutoxy) carbonyl) amino) methyl) -1 -methyl-1 Η-1,2,3 -triazo l-4-yl) -2 methylpyridin-3 yl)oxy)cyclohexane-1 -carboxylic acid LCMS, [M + H] ⁺ = 472.2; Ή NMR (500 MHz, DMSOU) δ 7.83 (d, J= 8.5 Hz, 1H), 7.49 (d, 7=8.6Hz, 1H), 7.41 (brs, 1H), 4.88-4.79 (m, 1H), 4.74 (s, 3H), 4.05 (s, 3H), 2.45 (s, 3H), 2.14-1.46 (m, 12H), 1.08 (s, 6H). (Proton a to carboxylic acid is not observed due to water suppression); hLPAi 1C ₅₀ = 90 nM. Example 1 169 οΛγΟΗ ⁰ 0Ν T O AT^nA-^ f Ν-Ν Η ° ^^l/F F (1 S,3 S)-3 -((2-methyl-6-( 1-methyl-5 ((((4 ,4,4-trifluorobutoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 500.1; Ή NMR (500 MHz, DMSOU) δ 7.84 (d, J= 8.5 Hz, 1H), 7.47 (d, 7= 8.6 Hz, 1H), 4.77 (d, 7= 5.4 Hz, 3H), 4.06 (s, 3H ), 4.01 (1.7=6.4Hz, 2H), 2.70-2.62 (m, 1H), 2.46 (s, ZH), 2.32-2.19 (m, 2H), 2.07-1.47 (br, YuN); hLPAi 1C ₅₀ = 55 nM. Example 1 170 Λ'Υ ^0Η [Υ ⁰ T O _ Ν.^Ν Ay Ν-Ν^ Η ^υ (1 S,3 S)-3 -((2-methyl-6-( 1-methyl-5 ((((( (R) -3 -methylbutan-2 -yl)oxy) carbonyl)amino)methyl)- 1H-1,2,3tr iazol-4-yl)pyridin-3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.2; Ή NMR (500 MHz, DMSO7,) δ 7.84 (d, 7= 8.6 Hz, 1H), 7.48 (d, 7= 8.6 Hz, 1H), 4.76 (d, 7= 11.4 Hz, 3H), 4.48 (s, 1H), 4.05 (s, 3H), 2.71–2.59 (br, 1H), 2.46 (s, 3H), 2.07 1.45 (br, 9H), 1.11–0.95 (br, 3H), 0.80 (br s, 6H) ; hLPAi 1C ₅₀ = 92 nM. Example 1

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171 Ar ⁰ Τ ο _ VUnAx ν-ν η ^u \ (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 ((((((K) -pentan-2-yl )oxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 460.2; Ή NMR (500 MHz, DMSOό/ ₆ )δ7.84 (d, 7= 8.5 Hz, 1H), 7.48 (d, 7= 8.6 Hz, 1H), 4.75 (d, 7= 7.9 Hz, 3H), 4.67 ( s, 1H), 4.05 (s, W), 2.69 - 2.62 (br, 1H), 2.46 (s, W), 2.09 1.20 (w, 12H), 1.15-1.05 (w, W), 0.84 (t, 7 = 7.8 Hz, ZN); hLPAi 1C ₅₀ = 76 nM. Example 1 172 ₀ Ό γ ^0Η ° T 0 _ NN n ^u (18.38)-3-((6-(5-((((K)-sec-butoxycarbonyl)amino) methyl) -1 -methyl- 1H1, 2,3-triazo l-4 -yl) -2 -methyl-pyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.2; Ή NMR (500 MHz, DMSO7 ₆ )δ7.83 (d, 7= 8.5 Hz, 1H), 7.49 (p7=8.7Hz, 1H), 4.78 (s, 1H), 4.75 (s, 2H), 4.62 4.54 ( w, 1H), 4.05 (s, ZN), 2.66 - 2.59 (w, 1H), 2.45 (s, ZN), 2.06-1.39 (br, YuN), 1.11 (p7=6.2Hz, ZN), 0.81 (t , 7= 8.4 Hz, ZN); hLPAi 1C ₅₀ = 152 nM. Example 1 173 Ar pf ⁰ D / N T ° > YU nn η ^ο ρ (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 (((((8) -3-methylbutane -2-yl)oxy) carbonyl)amino)methyl)- 1H-1,2,3triazol-4-yl)pyridin-3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.1; Ή NMR (500 MHz, DMSO7 ₆ )δ7.83 (d, 7= 8.6 Hz, 1H), 7.52 (s, 1H), 7.48 (d,7=8.7 Hz, 1H), 4.78 (s, 1H), 4.75 (s, 2H), 4.51 - 4.43 (m, 1H), 4.04 (s, 3H), 2.66 - 2.59 (t, 1H), 2.45 (s, 3H), 2.06 - 1.40 (t, 9H), 1.06 (d , 7= 6.4 Hz, ZN), 0.81 (1.7=6.9 Hz, 6H); hLPAi 1C ₅₀ = 167 nM. Example 1

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174 A/™ ⁰ Υ 0 N-ν η ^{0 4} F trifluorohorap-2 -yl) oxy) carbonyl) amino) methyl) -1Η- 1,2,3-triazol-4-yl) pyridin-3 yl) oxy) cyclohexane-1-carboxylic acid LCMS, [M + Η] ⁺ = 486.2; Ή NMR (500 MHz, DMSOdd) δ 8.11 (s, 1H), 7.82 (d,7= 8.6 Hz, 1H), 7.47 (d, 7=8.7 Hz, 1H), 5.33-5.18 (m, 1H), 4.80 (d,7=5.1 Hz, 2H), 4.77 (s, 1H), 4.03 (s, 3H), 2.66 2.57 (m, 1H), 2.42 (s, 3H), 2.04-1.41 (m, 8H), 1.30 (d, 7= 6.6 Hz, ZN); hLPAi IC ₅₀ = 101 hM. Example 1 175 χ9'Υ ^{0Η 0} H/N T O Υτ^νΑ/Α ν-ν H ° (18.38)-3-((6-(5-((((8)-sec-butoxycarbonyl)amino) methyl) -1 -methyl-1H1,2,3 -triazo l-4 -yl) -2 -methyl-pyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 446.0; Ή NMR (500 MHz, DMSO7 ₆ )δ7.83 (d, 7= 8.6 Hz, 1H), 7.48 (d, 7= 8.5 Hz, 1H), 4.78 (s, 1H), 4.75 (s, 2H), 4.62 4.55 (m, 1H), 4.05 (s, 3H). 2.67-2.58 (m, 1H), 2.45 (s, 3H), 2.05 - 1.39 (m, 10H), 1.10 (s, 3H), 0.80 (s, 3H); hLPAi IC ₅₀ = 95 hM. Example 1 176 Ax[A°X°f N-y Η ° (1 S,3 S) -3 -((6-(5 -(((((S)-1 -cyclopropylethoxy)carbonyl)amino)methyl) -1 -methyl-1 Η-1,2,3 -triazo l-4-yl) -2 methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.2; *H NMR (500 MHz, DMSOJe) δ 7.62 (d, 7= 8.5 Hz, 1H), 7.27 (d, 7= 8.6 Hz, 1H), 4.55 (brs, 3H), 3.92 (s, 1H), 3.84 ( s, 3H), 2.46 - 2.39 (m, 1H), 2.24 (s, 3H), 1.85-1.21 (m, 8H), 0.97 (d, 7= 6.7 Hz, ZH), 0.72 (br s, 1H), 0.28 - -0.06 (m, 4H); hLPAi IC ₅₀ = 106 hM. Example 1 177 Ο^Ο'γΟΗ ySy ° T O Ν-Ν Η ^υ LCMS, [M + H] ⁺ = 444.2; Ή NMR (500 MHz, DMSO7 ₆ )δ7.82 (d, 7= 8.6 Hz, 1H), 7.52 (s, 1H), 7.47 (d, 7=8.6 Hz, 1H), 4.77 (br s, 2H), 4.71 (br s, 2H), 4.04 (s, 3H), 2.66 - 2.56 (m, 1H), 2.44 (s, 3H), 2.23 - 1.43 (m, 14H); Example 1

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(1 S,3 S)-3 -((6-(5 -(((cyclobutoxy carbonyl)amino) methyl) -1 -methyl- 1H1,2,3 -triazo l-4 -yl) -2 -methyl- pyridin3-yl)oxy)cyclohexane-1-carboxylic acid hLPAi IC ₅₀ = 148 nM. 178 x9m°n [Xi ° 1 ⁰ F ν-ν H ° (18.38)-3-((6-(5-((((3,3-difluorocyclobutoxy)carbonyl)amino)methyl) -1 -methyl- 1 Η-1,2,3 -triazo l-4-yl) -2 methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 480.1; Ή NMR (500 MHz, DMSOU) δ 7.83 (d, J= 8.5 Hz, 1H), 7.80 (s, 1H), 7.49 (d, J=8.7 Hz, 1H), 4.77 (br s, 4H), 4.04 ( s, 3H), 3.05-2.92 (m, 2H), 2.62-2.52 (m, 3H), 2.45 (s, 3H), 2.04-1.43 (m, 8H); hLPAi IC ₅₀ = 102 nM. Example 1 179 ΧίΛ Chi ° T ⁰ ν-ν Η ^υ (1 S,3 S)-3 - ((2-methyl-6-( 1-methyl-5 (((((2-methylcyclopropyl) methoxy) carbonyl) amino) methyl )- 1H-1,2,3triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.4; Ή NMR (500 MHz, DMSOU) δ 7.62 (d, J= 8.5 Hz, 1H), 7.34 (s, 1H), 7.28 (d, J=8.6 Hz, 1H), 4.55 (br s, 3H), 3.85 ( s, 3H), 3.57 (d, J= 7.3 Hz, 2H), 2.44 - 2.35 (m, 1H), 2.24 (s, 3H), 1.81-1.25 (m, 8H), 0.75 (d, J= 6.0 Hz , ZN), 0.58 - -0.03 (m, 4H); hLPAi IC ₅₀ = 46 hM. Example 1 180 Ag (1 s,3 S)-3 -((6-(5 -(((((2,2-difluorocyclopropyl)methoxy)carbonyl)amino)methyl)-1 -methyl- 1H-1,2,3triazo l- 4 -yl) -2 -methylpyridin-3 yl)oxy)cyclohexane-1 -carboxylic acid (diastereomers at cyclopropyl carbon) LCMS, [M + H] ⁺ = 480.3; Ή NMR (500 MHz, DMSOU) δ 7.84 (d, J= 8.5 Hz, 1H), 7.73 (s, 1H), 7.48 (d, J=8.6 Hz, 1H), 4.79 (br s, 3H), 4.22 - 4.14(m, 1H), 4.06 (s, 3H), 3.87 (t, J= 10.2 Hz, 1H), 2.68 - 2.58 (m, 1H), 2.45 (s, 3H), 2.10-1.29 (m, 11H) ; hLPAi IC ₅₀ = 53 hM. Example 1

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181 A _r ^0H ° D / N 1 o Ν-N \ n _f (1 S,3 S)-3 - ((2-methyl-6-( 1 -methyl-5 ((((3,3,3 -trifluorohoroxy )carbonyl)amino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 486.1; Ή NMR (500 MHz, DMSOА) δ 7.84 (d, J= 8.8 Hz, 1H), 7.73 (s, 1H), 7.49 (d,7 = 8.7 Hz, 1H), 4.79 (d, 7= 5.2 Hz, 3H ), 4.19(s, 2H), 4.05 (s, 3H), 2.67-2.58 (m, 3H), 2.45 (s, 3H), 2.06-1.46 (m, 8H); hLPAi IC ₅₀ = 96 hM. Example 1 182 οΌγΟΗ Chi ⁰ Α,Ν X ° VOA ^N ~ ^N \ n ° _F F (1 S,3 S) -3 - ((6- (5 - (((((3,3-difluorocyclobutyl) methoxy) carbonyl) amino ) methyl)-1 -methyl-1 Η-1,2,3 -triazol-4 yl) -2-methylpyridin-3 -yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 494.3; Ή NMR (500 MHz, DMSOA) δ 7.84 (d, J= 8.5 Hz, 1H), 7.67 (s, 1H), 7.49 (d, 7=8.6 Hz, 1H), 4.79 (br s, 3H), 4.06 ( s, 3H), 4.03 (d, J= 6.0 Hz, 2H), 2.69 - 2.59 (m, 3H), 2.46 (s, 3H), 2.43 - 2.27 (m, 3H), 2.07 - 1.46 (m, 8H) ; hLPAi IC ₅₀ = 85 hM. Example 1 183 Pt ° ^H ° X ° <Y ^ nA N-Ν N ° 'gM (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 - (((((trans-2 -methylcyclopropyl) methoxy) carbonyl) amino) methyl) -1H1,2,3-triazol-4-yl) pyride in-3-yl) oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.3; Ή NMR (500 MHz, DMSOA) δ 7.65 (d, J= 8.5 Hz, 1H), 7.28 (d, 7= 8.6 Hz, 1H), 4.55 (br s, 3H), 3.87 (s, 3H), 3.60 ( d, 7 = 7.1Hz, 2H), 2.512.39 (m, 1H), 2.27 (s, 3H), 1.87- 1.26 (m, 8H), 0.77 (d, 7= 6.0 Hz, 3H), 0.55 (s , 1H), 0.44 (s, 1H), 0.22-0.14 (m, 1H), 0.03 (dd, 7= 8.7, 4.5 Hz, 1H); hLPAi IC ₅₀ = 32 hM. Example 1

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184 Ar rY ° D/NT O a NN Η ^ϋ (1 S,3 S)-3 -((6-(5 -((((2-cyclopropyl propoxy)carbonyl)amino)methyl) -1 methyl- 1H-1 ,2,3-triazol-4-yl)-2methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 472.4; Ή NMR (500 MHz, DMSOD) 5 7.84 (d, J= 8.6 Hz, 1H), 7.54 (s, 1H), 7.49 (d, J=8.7 Hz, 1H), 4.78 (s, 1H), 4.75 (d , J= 5.1 Hz, 2H), 4.06 (s, ZH), 4.01-3.95 (m, 1H), 3.843.78 (m, 1H), 2.63 (t, J= 11.1 Hz, 1H), 2.45 (s, 3H), 2.06 1.44 (m, 8H), 0.97 (br s, 1H), 0.89 (br s, 3H), 0.50 (br s, 1H), 0.37 - 0.25 (m, 2H), 0.08 (s, 1H) , 0.01 (s, 1H); hLPAi IC ₅₀ =41 hM. Example 1 195 Ο<θγΟΗ cSi ° H/N X ^{0 n} Yvn v\ NN H ^U (1 S,3 S)-3 -((2-methyl-6-( 1 -methyl-5 -((((2- (1 - methylcyclopropyl)ethoxy)carbonyl)amino)methyl)-1H-1,2,3triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 472.3; Ή NMR (500 MHz, DMSOD) δ 7.67 (d, J= 8.5 Hz, 1H), 7.34 (d, 7= 8.5 Hz, 2H), 4.66 -4.53 (m, 3H), 3.94-3.84 (m, 5H) , 1.89-1.20 (m, 10H), 0.82 (s, 3H), 0.08 (s, 2H), -0.00 (d, J= 4.4 Hz, 2H). (Proton a to carboxylic acid and -CH3 on pyridine is not observed due to water suppression); hLPAi 1C ₅₀ = 72 nM. Example 1 196 οΌγΟΗ cSx ⁰ D/N X ⁰ Ν-Ν _χ H ° F (IS,38)-3-((6-(5-((((4,4-difluoro-2methylbutoxy)carbonyl)amino)methyl) -1 - methyl-1 Η-1,2,3-triazo l-4-yl) -2 methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 496.2; Ή NMR (500 MHz, DMSOD) δ 7.85 (d, 7= 8.5 Hz, 1H), 7.64 (s, 1H), 7.50 (d, 7=8.6 Hz, 1H), 6.16 (t, 7 = 56.5 Hz, 1H ), 4.80 (br s, ZN), 4.06 (s, ZN), 3.91-3.81 (m, 2Н), 2.64 (t, J= 10.9 Hz, 1Н), 2.46 (s, ZN), 2.08-1.44 (m , PN), 0.93 (φ7=6.5Hz, ZN); hLPAi 1C ₅₀ = 83 nM. Example 1

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197 Ar [Ά ⁰ X ⁰ 'ii A mJ ν-Ν\ Η ° (1 S,3 S)-3 -((6-(5 -((((isopentyloxy) carbonyl)amino) methyl) -1 -methyl- 1H1,2,3 -triazo l-4 -yl) -2 -methyl-pyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 460.3; Ή NMR (500 MHz, DMSO7)5 7.82 (d, J= 8.4 Hz, 1H), 7.52 (d,7= 8.3 Hz, 2H), 4.74 (br s, 3H), 4.05 (s, 3H), 4.0 3.94 (w, 2H), 2.43 (s, ZN), 1.93 - 1.34 (w, PN), 0.85 (d, 7= 6.6 Hz, 6H). (Proton a to carboxylic acid is not observed due to water suppression); hLPAi 1C ₅₀ = 16 nM. Example 1 198 Ac [A ° Y O nn n ° ^X F (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 ((((2,2,3,3,3-pentafluoropropoxy ) carbonyl) amino) methyl) - 1H-1,2,3triazol-4-yl) pyridin-3 -yl) oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 522.3; Ή NMR (500 MHz, DMSO7) 5 8.23 - 8.13 (br, 1H), 7.85 (d,7= 8.5 Hz, 1H), 7.49 (d, 7= 8.7 Hz, 1H), 4.85 (d,7 = 5.3 Hz , 2H), 4.81-4.70 (br, 3H), 4.05 (s, 3H), 2.63 (t,7 = 11.3 Hz, 1H), 2.07-1.44 (t, 8H); hLPAi 1C ₅₀ = 45 nM. Example 1 199 ο*ΟγθΗ lSx ⁰ X ⁰ Ν-Ν H ° O (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 (((((4-oxopentyl) oxy) carbonyl) amino)methyl)-1H-1,2,3-triazol-4yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 473.9; Ή NMR (500 MHz, DMSO7)5 7.84 (d, 7= 8.4 Hz, 1H), 7.49 (d, 7= 8.6 Hz, 1H), 7.42 (s, 1H), 4.75 (s, 2H), 4.74 (s , 1H), 4.06 (s, 3H), 3.92 (t, 7= 6.6 Hz, 2H), 2.66 - 2.58 (t, 1H), 2.46 (s, 3H), 2.44 -2.39 (t, 2H), 2.05 ( s, ZN), 2.02 1.48 (t, YuN); hLPAi 1С ₅₀ =312nM. Example 1

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200 ₀ Pd it A ⁰ ίηΑ ⁴ F (lS,3S)-3 -((6-(5 -((((2,2-difluoropropoxy)carbonyl)amino)methyl) -1 methyl- 1H-1,2, 3-triazol-4-yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 468.2; Ή NMR (500 MHz, DMSOd ₆ ) δ 7.93 (s, 1H), 7.84 (d,J= 8.5 Hz, 1H), 7.48 (d,7=8.7 Hz, 1H), 4.81 (d, J= 5.3 Hz, 2H), 4.78 (brs, 1Н), 4.25(t, 7 = 13.5 Hz, 2H), 4.05 (s, ZN), 2.67 - 2.59 (m, 1Н), 2.45 (s, ZN), 2.05 - 1.45 (m , 11H); hLPAi IC ₅₀ = 82 nM Example 1 201 х9Г ⁿ А ⁰ Ν-Ν\ η ° (1 S,3 S)-3 -((2-methyl-6-( 1-methyl-5 ((((spiro [2.3] hexane-5 -yloxy) carbonyl) amino)methyl)-1H-1,2,3triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 470.3; Ή NMR (500 MHz, DMSOde) δ 7.58 (d, J= 8.5 Hz, 1H), 7.37 (s, 1H), 7.25 (d,7=8.6 Hz, 1H), 4.75 (br s, 1H), 4.50 ( d, J= 14.8 Hz, ZN), 3.80 (s, ZN), 2.20 (s, ZN), 2.03 - 1.18 (m, 12H), 0.23 - 0.07 (m, 4H). (Proton a to carboxylic acid is not observed due to water suppression); hLPAi 1C ₅₀ = 42 nM. Example 1 202 DAN Jib ⁰ D/N Ν-Ν\ η _f (IS,38)-3-((6-(5-((((3,3-difluorobutoxy)carbonyl)amino)methyl)-1 methyl- 1H- 1,2,3-triazol-4-yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 482.3; Ή NMR (500 MHz, DMSO7 ₆ )δ7.83 (d, 7= 8.6 Hz, 1H), 7.63 (s, 1H), 7.48 (d, 7=8.7 Hz, 1H), 4.77 (d, 7= 5.4 Hz , ZN), 4.11 (t, 7=6.5 Hz, 2Н), 4.04 (s, ЗН), 2.62 (t, 7= 11.0 Hz, 1Н), 2.44 (s, ЗН), 2.24 1.46 (m, 13Н); hLPAi 1C ₅₀ = 86 nM. Example 1

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203 ο Ο _ν θΗ Λ ° Ν.Λ J ^NN \ / ^N O ^., (1 S,3 S) -3 -((6-(5 -(((isobutoxycarbonyl)(methyl)amino)methyl) -1 methyl- 1H-1,2,3-triazol-4-yl)-2methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ = 460.3; Ή NMR (500 MHz, DMSOde) δ 7.84 (d, 7=8.5 Hz, 1H), 7.47 (d,7=8.7 Hz, 1H), 5.12 (s, 2H), 4.79-4.72 (m, 1H), 4.01 (s, 3H), 3.83 (d, 7=6.5 Hz, 2H), 2.76 (s, 3H), 2.68 2.59 (m, 1H), 2.44 (s, 3H), 2.04-1.47 (m, 9H), 0.87 (d, 7=6.6 Hz, 6H); hLPAi IC ₅₀ = 91 hM. Example 2 204 „LA, /OH C |G y“ τΓ'Λ-γΛ; (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 ((((3,3,3-trifluoro-2-methyl propoxy) carbonyl) amino) methyl) - 1H- 1,2,3tr iazo l-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid A mixture of diastereomers at -CH, LCMS, [M+H] ⁺ = 500.3; Ή NMR (500 MHz, DMSOde) δ 7.84 (br d, 7=8.5 Hz, 1H), 7.76 (brs, lH), 7.50(d, 7=8.5 Hz, 1H), 4.88-4.69 (m, 3H), 4.17-4.00 (m, 5H), 2.66 - 2.58 (m, 1H), 2.45 (s, 3H), 2.06 - 1.45 (m, 9H), 1.07 (br d, 7=7.0 Hz, ZN); hLPAi IC ₅₀ = 96 hM. Example 1

(1 S,3 S)-3 -((6-(5 -((((cyclopropyl methoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1 Η-1,2,3-triazole-4 yl)-2-methyl-pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid, TFA salt

LC-MS, [M+H] ⁺ = 458.2;

Ή NMR (500 MHz, DMSOde) 7.87 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 5.15 (s, 2H), 4.83 - 4.73 (m, 1H), 4.03 ( s, 3H), 3.89 (brd, J=7.2 Hz, 2H), 2.76 (br s, 3H), 2.70 -2.58(m, 1H), 2.45 (s, 3H), 2.09-1.97 (m, 1H), 1.93 1.75 (m, 3H), 1.71-1.45 (m, 4H), 1.18-1.01 (m, 1H), 0.57-0.43 (m, 2H), 0.32-0.19 (m, 2H). 30 out of 31 protons detected;

hLPAi IC ₅₀ = 333 nM.

Example 206 (1S,3S)-3-((6-(5-(((((4,4-Difluoropentyl)oxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3triazole -4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

206A. Methyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-((((4-oxopentyl)oxy)carbonyl)amino)methyl)-1H1,2,3-triazole- 4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of methyl (1S,3 S)-3 -((6-(5-(aminomethyl)-1 -methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy )cyclohexane-1-carboxylate (synthesized in the same way as Example 1H, except using (1S,3R)-methyl 3-hydroxy-cyclohexanecarboxylate rather than isopropyl ether; 25 mg, 0.070 mmol) and 4-nitrophenyl-(4 -oxopentyl) carbonate (22 mg, 0.083 mmol) in THF (0.2 ml) was added iPr ₂ NEt (0.036 ml, 0.209 mmol). The mixture was stirred at room temperature for 52 hours then concentrated in vacuo. The residue was subjected to chromatography (12 g SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes over 19 min, hold for 5 min) to give the title compound (31 mg, 0.064 mmol, 91% yield) as a colorless oil .

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1Н NMR (500 MHz, CDCI3) δ 8.05 (d, J=8.6 Hz, 1H), 7.27 (s, 1H), 7.07 (br s, 1H), 4.75 (dq, J=5.0, 2.6 Hz,

1H), 4.63 (d, J=5.4 Hz, 2H), 4.23 (s, 3H), 4.07 (t, J=6.3 Hz, 2H), 3.73 (s, 3H), 2.86 (tt, J=10.3, 3.9 Hz, 1H), 2.57 (s, 3H), 2.50 (t, J=7.2 Hz, 2H), 2.19-1.61 (m, 13H).

LCMS [M+H]+ = 488.1.

Example 206.

To a solution of the compound from example 206A (25 mg, 0.051 mmol) in DCM (0.5 ml) was added DAST (0.027 ml, 0.205 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h, then quenched with water (0.5 ml) and concentrated in vacuo. The residue was dissolved in THF (1 ml) and water (0.5 ml) and LiOH·H ₂ O (22 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature overnight, then adjusted to pH ~5 with 1N. aq. HCl and extracted with EtOAc (3x2 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by preparative LC/MS (column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 95:5 MeCN:H ₂ O with 0.1% TFA; gradient: 10-55% B over 19 min, then hold for 5 min at 100% B; flow rate: 20 ml/min). Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (17.2 mg, 0.027 mmol, 53% yield; LCMS purity = 97%).

LCMS [M+H]+ = 496.3.

1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 4.77 (d, J=5.5 Hz, 3H), 4.07 (s, 3H), 3.99 (t, J=6.5 Hz, 2H), 2.70-2.61 (m, 1H), 2.42 (s, 3H), 2.06-1.47 (m, 15H).

hLPA1 IC ₅₀ = 71 nM.

Example 207 (1S,3S)-3-((6-(5-((((((R)-2,2-Difluorocyclonronyl)methoxy)carbonyl)amino)methyl)-1methyl-1H-1,2, 3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)-cyclohexane-1-carboxylate, diethylammonium salt (first eluting isomer; stereochemistry of cyclopropyl chiral center is arbitrary)

Example 208 (1S,3S)-3-((6-(5-(((((S)-2,2-Difluorocyclopropyl)methoxy)carbonyl)amino)methyl)-1methyl-1H-1,2, 3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate, diethylammonium salt (second eluting isomer; stereochemistry of cyclopropyl chiral center is arbitrary)

The individual diastereomers of Example 180 were separated by SFC (column: Chiralpak AD-H, 21x250 mm, 5 µm; flow rate: 45 ml/min; oven temperature: 40° C.; BPR parameters: 150 bar; UV wavelength: 255 nm, mobile phase: 90% CO ₂ /10% MeOH - 0.1% DEA (isocratic mode) injection: 0.5 ml ~14 mg/ml in MeOH:MeCN) to give two diastereomers. The chiral purity of both compounds was determined to be >93% ee under these analytical conditions: column: Chiralpak AD-H, 4.6x250 mm, 5 µm (analytical); flow rate: 2 ml/min; thermostat temperature: 40°С; BPR parameters: 150 bar; UV wavelength: 254 nm; mobile phase: 10% MeOH - 0.1% DEA/85% CO ₂ (isocratic mode).

Example 207 First eluting enantiomer: LCMS [M+H]+ = 480.2. hLPA1 IC ₅₀ = 44 nM.

Example 208 Second eluting enantiomer: LCMS [M+H] ⁺ = 480.2. hLPA1 IC ₅₀ = 57 nM.

Example 209 (±)-cis-3-((6-(5-((((Benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4yl)-2- methylpyridin-3 -yl)oxy)-1-fluorocyclohexanecarboxylic acid

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209A. (±)-cis-Isopropyl 1-fluoro-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)-cyclohexanecarboxylate

Ph ₃ P (0.317 ml, 1.268 mmol) and (E)-diazene-1, 2-diylbis-(piperidin-1-ylmethanone) (0.320 g, 1.268 mmol). The reaction mixture was stirred at 50°C for 5 h, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The crude oil was chromatographed (24 g SiO ₂ ; continuous gradient from 0 to 50% EtOAc in hexane over 10 min) to give the title compound (0.06 g, 0.122 mmol, 19.29% yield) as a clear oil .

¹ H NMR (500 MHz, CDCl3) δ 7.86 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 5.31-5.17 (m, 2H), 5.04 (dt, J=12.4 , 6.3 Hz, 1H), 4.72-4.66 (m, 1H), 4.64-4.57 (m, 1H), 4.07 (s, 3Н), 3.82 (tt, J=8.5, 2.5 Hz, 1H), 3.49-3.42 ( m, 1H), 2.42 (s, 4H), 2.08-1.39 (m, 13H), 1.24 (dd, J=6.2, 2.6 Hz, 6H).

209B. (±)-cis-Isopropyl 1-fluoro-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2methylpyridin-3-yl)oxy )cyclohexanecarboxylate

A mixture of the compound from example 209A (0.18 g, 0.367 mmol) and p-TsOH (0.021 g, 0.110 mmol) in MeOH (10 ml) was stirred at 60°C for 3 h, then cooled to room temperature and NaHCO ₃ was added (0.031 g, 0.367 mmol). The mixture was stirred at room temperature for 1 h, then DCM (10 ml) was added. The mixture was filtered; the filtrate was concentrated in vacuo. The crude oil was chromatographed (12 g SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexane over 14 min) to give the title compound (0.133 g, 0.327 mmol, 89% yield) as a clear oil.

1H NMR (500 MHz, CDCl ₃ ) δ 7.22-7.18 (m, 1H), 5.03 (spt, J=6.3 Hz, 1H), 4.74 (d, J=1.1 Hz, 2H), 4.65 (quin, J=5.0 Hz, 1H), 3.99 (s, 3H), 2.44 (s, 3H), 2.40-2.28 (m, 1H), 2.12-1.76 (m, 6H), 1.52-1.41 (m, 1H), 1.23 (dd, J=6.3, 2.8 Hz, 6H);

¹⁹ F NMR (471 MHz, CDCl ₃ ) δ -153.01 (s, 1F).

209C. (±)-cis-Isopropyl 3-((6-(5-((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol4-yl)-2-methylpyridine- 3-yl)oxy)-1-fluorocyclohexanecarboxylate

A solution of Example 209B (33 mg, 0.081 mmol), benzyl N[(t-butoxy)carbonyl]carbamate (30.6 mg, 0.122 mmol), n-Bu ₃ P (0.030 mL, 0.122 mmol) and 1.1 '-(azodicarbonyl)dipiperidine (31 mg, 0.122 mmol) in toluene (2 ml) was stirred at 50°C for 3 h, then cooled to room temperature. TFA (1 ml) was added and the reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The crude oil was purified by preparative HPLC (Sunfire C18 30x100 mm column; detection at 220 nm; flow rate: 40 ml/min; continuous gradient from 20% B to 100% B over 10 min + 2 min hold at 100% B, where A = 90:10:0.1 H ₂ O:MeCN:TFA and B = 90:10:0.1 MeCN:H ₂ O:TFA) to give the title compound (40 mg, 0.074 mmol, 91% yield) as a clear oil.

[M+H]+ = 540.3.

Example 209.

A mixture of the compound from example 209C (40 mg, 0.074 mmol) and 2.0 M aq. LiOH (1.86 ml, 3.71 mmol) in THF (3 ml) was stirred at room temperature for 3 h. The product was purified by preparative HPLC (Sunfire C18 30x100 mm column; detection at 220 nm; flow rate: 40 ml/min ; continuous

- 125 042829 gradient from 20 to 100% B over 10 min + 2 min hold at 100% B where A = 90:10:0.1

H ₂ O:MeCN:TFA and B=90:10:0.1 MeCN:H ₂ O:TFA) to give the title compound (37.1 mg, 0.058 mmol, 79% yield) as a clear oil.

[M+H] ⁺ = 498.2.

1i NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.93 (br. s., 1H), 4.59 (s, 2H), 4.16 (s, 3H), 2.68 (s, 3H), 2.45-2.29 (m, 1H), 2.25-1.87 (m, 7H), 1.68 (br. s., 1H);

¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -154.52 (s, 1F).

hLPA1 IC ₅₀ = 12 nM.

Example 210 (1 R,3 S)-3-((6-(5-((((Benzyloxy)carbonyl)amino)methyl)-1-methyl-1 N-1,2,3-triazol-4yl) -2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic acid

Example 211 (1S,3R)-3-((6-(5-((((Benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4yl)-2- methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic acid

The absolute stereochemistry of the compounds of Examples 210 and 211 has not been determined - the stereochemistry in the structures shown is arbitrary. The two single enantiomers from Example 209 (32 mg, 0.064 mmol) were obtained by chiral SFC separation: instrument: Berger MGII-SFC, column: Chiralpak IC, 21x250 mm, 5 µm, mobile phase: 20% MeOH/80% CO ₂ , conditions flow: 45 ml/min, 150 bar, 40°C; detector wavelength: 254 nm, injection volumes: 0.5 ml solution of 8 mg/ml in MeOH:MeCN (1:1).

Example 210 - first eluting enantiomer (8.4 mg, 0.017 mmol, 25% yield); [M+H]+ = 498.1; 1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (br. s., 1H), 7.32 (br. s., 6H), 5.08 (br. s., 2H), 4.92-4.50 (m, 3H), 4.21 (br. s., 2H), 2.52 (br. s., 4H), 2.32-1.27 (m, 8H); ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -149.29 (s, 1F); hLPAi IC ₅₀ = 5 nM.

Example 211 - second eluting enantiomer (11 mg, 0.022 mmol, 33.7% yield); [M+H] ⁺ = 498.1; 1H NMR (400 MHz, CDCl3) δ 8.06 (br. s., 1H), 7.32 (br. s., 6H), 5.08 (br. s., 2H), 4.92-4.50 (m, 3H), 4.21 ( br. s., 2H), 2.52 (br. s., 4H), 2.32-1.27 (m, 8H); ¹⁹ F NMR (377 MHz, CDCl3) δ -150.17 (s, 1F); hLPA1 IC ₅₀ = 192 nM.

Intermediate 40 2,5-Dibromo-3-fluoro-6-methylpyridine

Intermediate 40A. 3-Fluoro-6-methylpyridine-2-amine

To a solution of 2-bromo-3-fluoro-6-methylpyridine (5.0 g, 26.3 mmol) in ethylene glycol (50 ml) and aq. 28% NH ₄ OH (63 ml; 450 mmol) was added Cu ₂ O (0.19 g, 1.32 mmol), K ₂ CO ₃ (0.73 g, 5.26 mmol) and N1,N1-dimethylethane- 1,2-diamine (0.29 ml, 2.63 mmol). The reaction mixture was purged with N ₂ then heated at 80° C. overnight in a sealed tube, after which it was cooled to room temperature and extracted with CH ₂ Cl ₂ (3 times). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was subjected to chromatography (SiO ₂ ; continuous gradient of 0-100% EtOAc in hexane) to give the title compound (2.81 g, 85% yield).

'and NMR (500 MHz, CDCl ₃ ) δ 7.11 (dd, J=10.6, 8.1 Hz, 1H), 6.47 (dd, J=8.0, 3.0 Hz, 1H), 4.55 (br s, 2H), 2.38 (s , 3H).

Intermediate connection 40V. 5-Bromo-3-fluoro-6-methylpyridin-2-amine

To a solution of intermediate 34A (3.91 g, 31.0 mmol) in CH ₃ CN (100 mL) at 0°C was added NBS (5.52 g, 31.0 mmol) in portions while maintaining the reaction temperature <5°С. The reaction mixture was stirred at room temperature for 30 min, then concentrated in vacuo. The residue was subjected to chromatography (SiO ₂ ; isocratic elution with 30% EtOAc in hexanes) to give the title compound (6.14 g, 97% yield).

1H NMR (500 MHz, CDCl3) δ 7.37 (d, J=9.6 Hz, 1H), 4.59 (br s, 2H), 2.48 (d, J=1.1 Hz, 3H).

Intermediate 40.

To a solution of aq. 48% HBr (23.7 ml, 210 mmol, 48%) at 0° C. was slowly added in portions of Intermediate 34B (6.14 g, 29.9 mmol). Br ₂ (3.09 ml, 59.9 mmol) was added dropwise while maintaining the reaction temperature <5°C. The reaction mixture was stirred at 0°C for 30 min, after which a solution of NaNO ₂ (5.17 g, 74.9 mmol) in water (10 ml) was added dropwise, maintaining the reaction temperature <5°C. The reaction mixture was stirred for 30 min at 0° C., then poured into ice water, basified with 50% aq. NaOH and extracted with EtOAc (2 times). The combined organic extracts were washed with aq. 10% Na ₂ S ₂ O ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (SiO ₂ ; continuous gradient 0-25% EtOAc in hexanes) to give the title compound (3.90 g, 48% yield).

1H NMR (500 MHz, CDO3) δ 7.60 (d, J=6.6 Hz, 1H), 2.64 (d, J=1.4 Hz, 3H).

Intermediate 41 Isopropyl (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3triazol-4-yl)-5-fluoro-2-methylpyridin-3 -yl)oxy)cyclohexane-1-carboxylate

Intermediate 41 was prepared using the same synthesis sequence as used to prepare the compound of Example 1E, except that Intermediate 40 was used instead of 2,5-dibromo-6-methylpyridine, which was used to synthesize the compound of Example 1A.

LCMS [M+H]+ = 407.

¹ H NMR (400 MHz, CDCl3) δ 7.16 (d, J=11.9 Hz, 1H), 5.05 (quin, J=12.5 Hz, 1H), 4.76 (s, 2H), 4.66 (m, 1H), 4.13 ( s, 3Н), 2.77 (m, 1H), 2.50 (d, J=1.1 Hz, 3Н), 2.07-2.02 (m, 2H), 1.97-1.86 (m, 2H), 1.81-1.62 (m, 4H) , 1.27 (dd, J=6.2, 3.7 Hz, 6H).

Intermediate 42 -triazole-5-carboxylic acid

Intermediate 42 was prepared using the same synthesis sequence as used to prepare the compound of Example 64B. In the synthesis sequence, intermediate 40 was used in place of 2,5-dibromo-6-methylpyridine.

Compounds of the examples in the following table were synthesized using the general procedures described for the preparation of the compounds of examples 1 and 64, and using intermediates 41 and 42; or compounds according to example 137.

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Etc. No. Structure and name Analytical and biological data Method 212 A ⁰ T ^{F 0} GUmH / D-L NN ^ H W (1 S,3 S) -3 - ((6- (5 - ((((cyclobutyl methoxy) carbonyl) amino) methyl) -1 methyl-1 Η -1,2,3 -triazo l-4-yl) -5 -fluoro -2 methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M+H] ⁺ =476; Ή NMR (500 MHz, Ή NMR (500 MHz, DMSO-de) 5 7.56 (d, 7=11.9 Hz, 1H), 7.49 (brs, 1H), 4.80 (br s, 1H), 4.58(br d, 7 =5.2 Hz, 2H), 4.07 (s, 3H), 3.92 -3.87 (m, 2H), 2.64 2.58 (m, 1H), 2.40 (s, 3H), 2.00-1.75 (m, 8H), 1.71 1.62 ( m, ZN), 1.59 - 1.50 (m, 2H); hLPAi IC50 = 112 nM. Example 1 with Intermediate 35 213 A ⁰ j ^{F 0} N-γ H | (1 S,3 S)-3 -((5-fluoro-6-(5 -(((isobutoxycarbonyl)amino)methyl) -1 -methyl1H-1,2,3-triazol-4-yl)-2- methylpyridin3-yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ =464; Ή NMR (500 MHz, DMSOde) 5 7.52 (d, 7=11.9 Hz, 1H), 7.46 (brs, 1H), 4.80 (brs, 1H), 4.56 (br d, 7=3.4 Hz, 2H), 4.06 ( s, 3H), 2.63 (m, 1H), 2.39 (s, 3H), 2.01 (m, 1H), 1.91–1.71 (m, 4H), 1.67–1.46 (m, 4H), 0.81 (brd, 7= 5.2 Hz, 6H); hLPAi IC50 = 382 nM. Example 1 with Intermediate 35

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214 xv X°AA N-N^ H (lS,3S)-3 -((5 -fluoro -2 -methyl-6 -(1 -methyl -5 ((((spiro[2.3]hexane-5 - yloxy)carbonyl)amino)methyl)-1H-1,2,3tr iazo l-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ =488; Ή NMR (500 MHz, DMSOde) δ 7.52 (br d, 7=10.4 Hz, 1H), 4.94(br, 1H), 4.8O (brs, 1H), 4.55 (br s, 2H), 4.06 (s, 3H ), 2.63 (m, 1H), 2.39 (s, 3H), 2.27-2.12 (m, 4H), 2.01 (m, 1H), 1.88-1.75 (m, 3H), 1.66-1.46 (m, 4H), 0.46 0.31 (m, 4H); hLPAi IC50 = 129 hM. Example 1 with Intermediate 35 215 A ^D ⁰ π η ΝχΧ A ^{F 0} JAT^ ⁴ nXaJ NN \ HA (lS,3S) -3 - ((5 -fluoro -2 -methyl-6 - (1 -methyl -5 (((((1 - methylcyclopropyl) methoxy) carbonyl) amino) methyl) -1H1,2,3-triazol-4-yl) pyride in-3-yl) oxy) cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ =476; Ή NMR (500 MHz, Ή NMR (500 MHz, DMSO-de) δ 7.50 (brd, 7=11.6 Hz, lH), 4.79(br s, 1H), 4.56 (br s, 2H), 4.06 (s, 3H ), 3.73 -3.63 (m, 1H), 2.62 (m, 1H), 2.38 (s, 3H), 2.04 1.97 (m, 1H), 1.89 - 1.75 (m, 3H), 1.66 - 1.46 (m, 5H) , 0.99 (br s, 3H), 0.37 (br s, 2H), 0.25 (br s, 2H), hLPAi IC ₅₀ = 112hM. Example 1 with Intermediate 35 216 Ό γ ^0Η ¥ ° A ° h¥ Ayy Ν-Ν ^ H A (1 S,3 S) -3 - ((6- (5- ((((( 1 -ethylcyclopropyl) methoxy) carbonyl) amino) methyl )-1-methyl- 1H-1,2,3-triazol-4-yl)-5 fluoro-2-methylpyridin-3 -yl) oxy)cyclohexane-1-carboxylic acid LCMS, [M+H] ⁺ =490; Ή NMR (500 MHz, Ή NMR (500 MHz, DMSO-de) δ 7.53 (brd, 7=12.2 Hz, lH), 4.79(br s, 1H), 4.57 (br s, 2H), 4.06 (s, 3H ), 3.76 (brs, lH), 2.59(m, lH), 2.38(s, 3H), 1.99–1.92 (m, 1H), 1.89–1.79 (m, 4H), 1.68–1.47 (m, 4H), 1.291.21 (m, 2H), 0.85 - 0.78 (m, 3H), 0.35 (br s, 2H), 0.26 (br s, 2H), hLPAi IC ₅₀ = 46 hM. Example 1 with Intermediate 35 217 ^D o π η Ν. 1 ^F X ⁿ nAn ^N -\ o LCMS, (M+H) ⁺ =450; Ή NMR (500 MHz, DMSOde) δ 7.95 (s, 1H), 7.50 (brd, 7=11.9 Hz, 1H), 4.80 (br s, 1H), 3.88 (s, 3H), 3.47 -3.30 ( brm, 2H ), 2.61 (m, 1H), 2.36 (s, 3H), 2.04-1.96 (m, 1H), 1.89-1.74 (m, 3H), 1.661.47 (m, 5H), 1.40-1.18 (br Example 64 and scheme 7 with intermediate connection 36

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(18.38)-3-[(6-{5-[(butoxycarbonyl)amino]-1-methyl-1 Η-1,2,3-triazol-4-yl } 5-fluoro-2-methylpyridine- 3 yl)oxy]cyclohexane-1-carboxylic acid w, 2H), 0.84 (br s, 3H); hLPAi 1C ₅₀ = 72 nM. 218 Ό _Υ ^ΟΗ a ° (1 S,3 S)-3 -{[6-(5-{[(cyclopropyl methoxy) carbonyl] amino } -1 -methyl-1H1,2,3-triazol-4-yl) -5-fluoro-2methylpyridin-3 -yl]hydroxy}cyclohexane-1 carboxylic acid LCMS, (M+H) ⁺ = 448.2; Ή NMR (500 MHz, DMSOde) δ 7.94 (s, 1H), 7.49 (brd, 7=12.2 Hz, 1H), 4.80 (br s, 1H), 3.89 (s, 3H), 2.61 (m, lH), 2.36(s, 3H), 2.03 - 1.96 (m, 1H), 1.89 - 1.73 (m, 3H), 1.65 - 1.45 (m, 4H), 1.170.94 (m, 1H), 0.47 (br s, 2H) , 0.22 (br s, 2H); hLPAi IC ₅₀ = 300 hM. Example 64 and scheme 7 with intermediate connection 36 219 a ° T ^F 1 n NN J ^V \ (18.38) -3- ((5-fluoro-6- (5 ((isobutoxycarbonyl) amino) -1 -methyl1H-1,2,3-triazol-4-yl )-2-methylpyridin3 -yl)oxy)cyclohexane-1-carboxylic acid LCMS, (M+H) ⁺ =450; Ή NMR (500 MHz, DMSOde) δ 7.95 (s, 1H), 7.50 (brd, 7=12.2 Hz, 1H), 4.81 (br s, 1H), 3.89 (s, 3H), 3.34 (m, 1H), 2.61 (m, lH), 2.36(s, 3H), 2.01 (m, 1H), 1.90-1.75 (m, 3H), 1.67-1.45 (m, 4H), 0.86 (m, 6H); hLPAi IC ₅₀ = 152 hM. Example 64 and scheme 7 with intermediate connection 36 220 ά ” kv ^Ν Λ O g (1 S,3 S) -3 - ((6- (5 - ((isopropoxycarbonyl) amino) -1 -methyl- 1H-1,2,3tr and azo l-4-yl) pyr idin-3-yl)oxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 404.3; Ή NMR (DMSO-de) δ: 8.26 (d, J=2.4Hz, 1H), 7.85 (d, 1=8.9Hz, 1H), 7.51 (dd, J=8.7, 2.6Hz, 1H), 4.74 (br s, 2H), 3.85 (s, 2H), 3.65-3.76 (m, 1H), 2.61 (brs, 1H), 1.70-1.97 (m, 4H), 1.45-1.70 (m, 4H), 1.17 (brs, 6H); hLPAi IC ₅₀ = 3 8 9 hM. Example 64 and scheme 7

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221 ά l " ^N - \ 0 (1 S,3 S) -3 - ((6- ( 1 -methyl-5 - ((propoxy carbonyl) amino) -1H-1,2,3-triazol-4yl) pyridine- 3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 404.1; Ή NMR (400 MHz, CDCL) δ 8.72 (d, 7=2.9 Hz, 1H), 8.38 (d, 7=9.0 Hz, 1H), 7.95 (dd, 7=9.1, 2.8 Hz, 1H), 5.56-5.44 (br, 1H), 4.84 (br s, 1H), 4.12 (t, 7=6.7 Hz, 2H), 4.08 (s, 3H), 3.00-2.91 (br, 1H), 2.342.21 (br, 1H) , 1.99 - 1.83 (br, 6Н), 1.74 - 1.65 (br, ZN), 0.97 (t, 7=7.5 Hz, ZN); hLPAi 1C ₅₀ = 42 nM. Example 64 and scheme 7 222 Ag A ⁰ m. ^N - \ o (1 S,3 S) -3 - ((6- (5 - ((butoxycarbonyl) amino) -1-methyl-1H-1,2,3-triazol-4-yl) -2methylpyridin-3 -yl)oxy) cyclohexane-1 carboxylic acid LCMS, [M - H] ⁺ = 432.2; Ή NMR (500 MHz, DMSOde) δ 7.83 - 7.67 (m, 1H), 7.50 -7.38(m, 1H), 4.87-4.68 (m, 1H), 4.11 -3.96 (m, 1H), 3.95 -3.81 (m , 3H), 2.72 - 2.62 (m, 1H), 2.57 - 2.54 (m, 3H), 2.46 - 2.33 (m, 3H), 2.14 - 1.97 (m, 1H), 1.92 - 1.73 (m, 3H), 1.69 -l.ll(m, 7H), 0.95 - 0.66 (m, 3H); hLPAi IC ₅₀ = 21 hM. Example 64 and scheme 7 223 Ar o bA 1 ^{n N} -\ ό' A (18.38)-3-((2-methyl-6-(1-methyl-5-((((2methylcyclopropyl)methoxy)carbonyl)amino)-1H-1 ,2,3-triazol-4yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid (mixture of cyclopropyl diastereomers) LCMS, [M - H] ⁺ = 444.0; Ή NMR (500 MHz, DMSOde) δ 7.57 - 7.44 (m, 1H), 7.31 -7.16(m, 1H), 4.73 -4.42 (m, 1H), 3.69 -3.54 (m, 3H), 2.45 -2.34 (m , 1H), 2.28–2.23 (m, 6H), 2.18–2.06 (m, 3H), 1.91–1.48 (m, 4H), 1.44–1.12 (m, 4H), 0.93–0.24 (m, 5H); hLPAi IC ₅₀ = 52 hM. Example 64 and scheme 7 224 _; Ό· _Υ » A ° xrV+J? ^Ν Λ O (1 S,3 S) -3 - ((2-methyl-6-( 1 -methyl-5 - ((((1 methylcyclopropyl) methoxy) LCMS, [M - H] ⁺ = 444.0; Ή NMR (500 MHz, DMSOde) δ 7.85 - 7.62 (m, 1H), 7.50 -7.35 (m, 1H), 4.88 -4.66 (m, 1H), 4.02 -3.85 (m, 3H), 3.04 -2.82 (m , 1H), 2.68-2.61 (m, 1H), 2.43 - 2.27 (m, 3H), 2.10 - 1.96 (m, 1H), 1.92-1.71 (m, 3H), 1.66-1.44 (m, 4H), 1.21 -0.86 (m, 5H), 0.61 -0.01 (m, 4H); hLPAi IC ₅₀ = 60 hM Example 64 and scheme 7

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carbonyl)amino)-1H-1,2,3-triazol-4yl)pyridin-3 -yl)oxy)cyclohexane-1 carboxylic acid 225 Ab™ Υξ ⁰ mLd (1 S,3 S)-3 -((2-methyl-6-( 1 -methyl-5 (((spiro [2.3] hexan-5 -yloxy) carbonyl) amino) -1H-1 ,2,3-triazol-4yl)pyridin-3-yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M-H] ⁺ = 456.0; Ή NMR (500 MHz, DMSOde) δ 7.78 - 7.62 (m, 1H), 7.51 -7.35 (m, 1H), 5.17-4.91 (m, 1H), 4.82 -4.67 (m, 1H), 3.99 -3.76 (m , 3H), 2.55(s, 4H), 2.41 -2.12 (m, 5H), 2.04 1.91 (m, 1H), 1.85 - 1.70 (m, 3H), 1.68 - 1.38 (m, 4H), 0.56 -0.19( m, 4H); hLPAi IC ₅₀ = 181 hM. Example 64 and scheme 7 226 X jun '|f / k / ⁰ 1 n η / N ^b ' _ Ν-Ν Η - \ Π \ (1 S,3 S) -3 - ((6-(5 - (((X- (cyclopentyl methyl )sulfamoyl)amino)methyl)-1methyl- 1H-1,2,3-triazol-4-yl)-2methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 507.2; Ή NMR (500 MHz, CDC1 ₃ ) δ 8.05 (brd, 7=8.8 Hz, 1H), 7.85 (brd,7=9.1 Hz, 1H), 4.85 (br s, lH), 4.50(s, 2H), 4.17 (s, 3H), 3.08-2.85 (m, 3H), 2.74 (s, 3H), 2.25-1.35 (m, 16H), 1.26-1.07 (m, 2H); hLPAi IC ₅₀ = 1105 hM. Example 137 227 X Λ, .OH g Ν-Ν Η N\n (1 S,3 S)-3 -((6-(5 -(((N-benzylsul famoyl)amino)methyl) -1 -methyl-1H1,2,3 -triazo l-4 -yl) -2 - methyl pyridin-3 yl)oxy)cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 515.0; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.00 (d, 7=8.8 Hz, 1H), 7.80 (d, 7=9.0 Hz, 1H), 7.36 - 7.27 (m, 5H), 4.82 (br s, 1H) , 4.34 (s, 2H), 4.21 (s, 2H), 4.02 (s, 3H), 2.94 - 2.83 (m, 1H), 2.70 (s, 3H), 2.19-1.61 (m, 8H); hLPAi IC ₅₀ = 1802 hM. Example 137

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228 A L, young 9 G Lo N0 / 0 (18.38)-3-((6-(5-(((X-benzyl-X-methylsulfamoyl)(methyl)amino)methyl)-1 methyl -1H-1,2,3-triazol-4-yl )-2methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 543.2; ^{1 H} NMR (500 MHz, DMSOde) δ 7.87 (brd, 7=8.5 Hz, 1H), 7.48 (br d, 7=8.5 Hz, 1H), 7.41 -7.28 (m, 5H), 5.06 (s, 2H) , 4.77 (br s, 1H), 4.36 (s, 2H), 4.08 (s, 3H), 2.71 (s, 3H), 2.64 (s, 4H), 2.43 (s, 3H), 2.01(br d, 7 =13.7 Hz, 1H), 1.91 - 1.73 (m, 3H), 1.68 - 1.45 (m, 4H); hLPAi IC ₅₀ = 218hM. Example 137 229 Λ A /OH '|f /k/ ° 1 II 0N nV V Ν-Ν / ^Ν (lS,3S)-3-((6-(5-(((X-butyl-X-methyl sulfamoyl)(methyl )amino)methyl)-1 methyl- 1H-1,2,3-triazol-4-yl)-2methylpyride in-3 -yl)oxy)cyclohexane-1 carboxylic acid LCMS, [M + H] ⁺ = 509.2; Ή NMR (500 MHz, DMSOde) δ 7.87 (brd, 7=8.5 Hz, 1H), 7.48 (br d, 7=8.9 Hz, 1H), 4.98 (s, 2H), 4.77 (br s, 1H), 4.05 (s, 3H), 3.13 (brt, 7=7.3 Hz, 2H), 2.78 (s, 3H), 2.69-2.59 (m, 1H), 2.57 (s, 3H), 2.44 (s, 3H), 2.01 ( brd,7=12.5 Hz, 1H), 1.89 - 1.73 (m, 3H), 1.68 - 1.44 (m, 6H), 1.31 - 1.21 (m, 2H), 0.88 (t, 7=7.3 Hz, ZN) hLPAi IC ₅₀ = PO nM Example 137 230 Αγ ^οΗ V ⁰ Ayu ^Ν Λ o (18.38) -3-{[2-ethyl-6-(1-methyl-5-{[(2methylpropoxy)carbonyl] amino } -1H1,2,3-triazole-4 -yl) pyridin-3yl] hydroxy} cyclohexane-1-carboxylic acid LCMS, (M+H) ⁺ = 446.3; Ή NMR (500 MHz, DMSOde) δ 7.73 (brd, 7=8.5 Hz, 1H), 7.43 (d, 7=8.6 Hz, 1H), 4.74 (br s, 1H), 3.91-3.85 (m, 3H), 3.84 -3.76 (m, 1H), 2.822.72 (m, 2H), 2.61 (brt, 7=10.5 Hz, 1H), 2.07-1.92 (m, 1H), 1.90-1.71 (m, 4H), 1.66- 1.45 (m, 5H), 1.22 (brt, 7=7.4 Hz, ZN), 0.81 (br s, 6H); hLPAi IC ₅₀ = 17 nM. Example 64 231 οΖ9 _γ °Η ⁰ II 1 N^yJ 1 ⁿ LCMS, (M+H) ⁺ = 444.4; Ή NMR (500 MHz, DMSOde) δ 7.73 (d, 7=8.5 Hz, 1H), 7.46 (br d, 7=8.5 Hz, 1H), 4.75 (br s, 1H), 3.94-3.79 (m, 4H) , 2.80-2.76 (m, 2H), 2.60 2.52 (m, 2H), 1.96 (brd, 7=13.1 Hz, 1H), 1.79 (brs, 4H), 1.66-1.46 (m, 5H), 1.23 (brt, 7=7.5 Hz, ZN), 0.48 (br s, Example 64

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(1S, 3 S)-3 - {[6-(5 -{[(cyclopropylmethoxy)carbonyl]amino} -1-methyl- 1H1,2,3-triazol-4-yl)-2-ethylpyridin-3yl]oxy } cyclohexane-1-carboxylic acid 2Н), 0.23 (br s, 1Н); hLPAi 1C ₅₀ = 28 nM. 232 Doo ° n 1 1 n Λ P (lS,3S)-3-[(6-{5-[(butoxycarbonyl)amino]-1-methyl-1 Η-1,2,3-triazol-4-yl} 2-ethylpyridin-3-yl)oxy ]cyclohexane-1 carboxylic acid LCMS, (M+H) ⁺ = 446.3; Ή NMR (500 MHz, DMSOde) δ 7.74 (d, 7=8.5 Hz, 1H), 7.45 (d, 7=8.5 Hz, 1H), 4.77 (brs, 1H), 3.89 - 3.85 (m, 3H), 2.78 (q, 7=7.6Hz, 2H), 2.60 (brt, 7=10.5Hz, 1H), 2.01 (br d, 7=13.7Hz, 1H), 1.85 (brd, 7=11.9Hz, 2H), 1.82- 1.71 (m, 2H), 1.64 - 1.45 (m, 7H), 1.23 (t, 7=7.5 Hz, 5H), 0.85 (br s, 3H); hLPAi IC ₅₀ = 12 nM. Example 64 233 Ar ⁰ I Η ν/τ VA/k Λ ο (1S, 3 S)-3-[(2-ethyl-b- {1-methyl-5 [(propoxycarbonyl)amino] - 1Η-1,2,3triazole- 4-yl}pyridin-3 yl)oxy]cyclohexane-1-carboxylic acid LCMS, (M+H) ⁺ = 432.1; Ή NMR (500 MHz, DMSOde) δ 7.72 (d, 7=8.5 Hz, 1H), 7.46 (d, 7=8.5 Hz, 1H), 4.72 (brs, 1H), 4.02 -3.95 (m, 1H), 3.93 - 3.83 (m, 3H), 2.78 (q, 7=7.5 Hz, 2H), 2.48 - 2.41 (m, 1H), 1.87 (br s, 2H), 1.74 (br d, 7=10.5 Hz, 2H), 1.67-1.47 (m, 6H), 1.23 (t, 7=7.5 Hz, 4H), 0.83 (br s, 3H); hLPAi IC ₅₀ = 1044 nM. Example 64

Example 234 (1S,38)-3-((2-Methyl-6-(1-methyl-5-((2-methyl-2-phenoxypropanamido)methyl)-1 H-1,2,3triazole-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

To a solution of 2-methyl-2-phenoxypropanoic acid (4.2 mg, 0.023 mmol) in DCM (0.3 ml) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (3 μl , 0.023 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated in vacuo. To the residue were added THF (0.3 ml), the compound of example 1H (6 mg, 0.015 mmol) and iPr ₂ NEt (5 μl, 0.03 mmol). The reaction mixture was stirred at room temperature for 1 h after which MeOH (0.2 ml), THF/water (0.5 ml each) and LiOH-H ₂ O (4 mg, 0.1 mmol) were added. The reaction mixture was stirred at room temperature overnight; the pH was adjusted to ~5 with 1N. aq. HCl. The mixture was extracted with EtOAc (3x2 ml). The combined organic fractions were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by preparative LC/MS (column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 95:5 MeCN:H ₂ O with 0.1% TFA, gradient: 21-61% B over 20 min, then hold for 4 min at 100% B, flow rate: 20 ml/min Fractions containing the desired product were combined and dried with The material was further purified using preparative LC/MS (column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 MeCN:H ₂ O with 10 mM aq. NH ₄ OAc; mobile phase B: 95:5 MeCN:H ₂ O with 10 mM aq NH ₄ OAc, gradient: 16-56% B over 25 min, then hold for 5 min at 100% B, flow rate: 20 ml/min. containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3.9 mg; 47% yield; LCMS purity = 95%).

LCMS [M+H]+ = 508.2.

Ή NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.02 (t, J=7.8 Hz , 2Н), 6.86 (t, J=7.3 Hz, 1H), 6.60 (d, J=8.0 Hz, 2Н), 4.73-4.66 (m, 3Н), 4.10 (s, 3Н), 2.49-2.43 (m, 1H), 2.31 (s, 3H), 1.91-1.46 (m, 8H), 1.36 (s, 3H), 1.35 (s, 3H).

hLPA1 IC ₅₀ = 392 nM.

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Example 235 (1S,3S)-3-((6-(5-((2-Cyclopentylacetamido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2methylpyridin-3 - yl)hydroxy)cyclohexanecarboxylic acid

O^^^'^COgH

U _u

Ν-γ n

235A. (1S,3 S)-Ethyl 3-((6-(5 -(aminomethyl)-1 -methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3 yl)oxy)cyclohexanecarboxylate

To a solution of (1S,3S)-ethyl 3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane carboxylate (20 mg, 0.054 mmol; prepared in the same manner as Intermediate 1H) and Et ₃ N (7.5 μl, 0.054 mmol) in DCM (3 ml) under N ₂ was added 2-cyclopentylacetyl chloride (9.4 mg , 0.064 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The crude title compound was used in the next reaction without further purification.

Example 235.

To a solution of Example 235A (20 mg, 0.041 mmol) in THF/MeOH (1.5 ml each) was added LiOH-H ₂ O (3 mg, 0.124 mmol) in water (1.5 ml). The reaction mixture was stirred for 14 h at room temperature, then diluted with water (20 ml), washed with Et ₂ O (10 ml) and neutralized with 1.5N. HCl (1.5 ml). The mixture was stirred with 5% MeOH in CHCl ₃ (20 ml) for 2 minutes. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Ascentis Express C18 (50x2.1 mm), 2.7 µm; mobile phase A: 5:95 MeCN:water with 10 mM aq. NH4OAc; mobile phase B: 95:5 MeCN:water with 10 mM aq NH4OAc, temperature: 50°C, gradient: 0-100% B over 3 min, flow rate: 1.1 ml/min) to give the title compound (8.7 mg, 0.019 mmol, yield 46.2%) as a clear oil.

[M+H]+ = 456.2.

¹ H NMR (400 MHz, CD3OD): δ 7.84 (d, J=8.40 Hz, 1H), 7.47 (d, J=8.80 Hz, 1H), 4.89 (s, 2H), 4.74-4.78 (m, 1H) , 4.16 (s, 3Н), 2.71-2.79 (m, 1H), 2.56 (s, 3Н), 2.10-2.21 (m, 3Н), 1.91-1.97 (m, 3Н), 1.49-1.78 (m, 11H) , 1.07-1.12 (m, 2Н).

hLPA1 IC ₅₀ = 105 nM.

The compounds of the examples in the following table were synthesized following the procedures described for the synthesis of the compound of example 235.

- 135 042829

Ex. No. Structure and name Analytical and biological data 236 sF 1 ° HA Ν-Ν ^H \ (1 S,3 S)-3 - ((6- (5 - ((2-cyclopentyl acetamido) methyl) -1 -methyl- 1H-1,2,3triazol-4 -yl) pyridin-3 -yl) hydroxy) cyclohexanecarboxylic acid LCMS, [M + H] ⁺ = 442.2; Ή NMR (400 MHz, CD ₃ OD): δ 8.42 (s, 1H), 8.00 (d, J = 9.20 Hz, 1H), 7.53 (dd, J - 2.40, 8.80 Hz, 1H), 4.74-4.79 (m , 1H), 4.52 (s, 2H), 4.20 (s, 3H), 2.78-2.84 (m, 1H), 2.06-2.20 (m, 3H), 1.90-2.02 (m, 3H), 1.49-1.84 (m , HH), 1.03-1.10 (m, 2H); hLPAi IC50 = 569 nM. 237 СХ I ⁰ Ν Ν-Ν ^H \ (1 S,3 S) -3 - ((2-methyl-6- ( 1 -methyl-5 (pentanamidomethyl) -1H-1,2,3triazol-4-yl) pyridine -3-yl)hydroxy)cyclohexanecarboxylic acid LCMS, [M + H] ⁺ = 430.2; Ή NMR (400 MHz, CD3OD): δ 7.84 (d, J = 8.40 Hz, 1H), 7.47 (d, J = 8.80 Hz, 1H), 4.89 (s, 2H), 4.74-4.78 (m, 1H), 4.16 (s, 3H), 2.71-2.79 (m, 1H), 2.56 (s, 3H), 2.21 (t, J - 7.60 Hz, 2H), 2.09-2.12 (m, 1H), 1.92-1.98 (m, 3H), 1.61-1.78 (m, 4H), 1.55 (p, 2H), 1.251.28 (m, 2H), 0.87 (t, J = 7.20 Hz, ZH); hLPAi IC50 - 783 nM.

Example 238 (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(2-(2-phenylacetamido)ethyl)-1H-1,2,3-triazol-4yl) pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

238A. Methyl (1 S,3S)-3-((6-(5-(hydroxymethyl)-1 -methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane- 1-carboxylate

The title compound was synthesized using the same procedures used to prepare intermediate 1E, except that (1S,3R)-methyl 3-hydroxycyclohexane carboxylate was used.

¹ H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 4.81 (s, 2H), 4.72 (dp, J=5.1, 2.7 Hz, 1H), 4.07 (s, 3H), 3.69 (s, 3H), 2.82 (tt, J=10.2, 3.9 Hz, 1H), 2.53 (s, 3H), 2.19-1.54 (m, 8H).

LC-MS, [M+H]+= 361.2.

238B. Methyl (1S,3S)-3-((6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane-1 -carboxylate

To a solution of the compound from example 238A (1.0 g, 2.77 mmol) in DCM (25 ml) at 0°C was added PBr ₃ (0.26 ml, 2.8 mmol). The reaction mixture was stirred at 0°C for 1 h, then neutralized

- 136 042829 by slowly adding a saturated aqueous solution of NaHCO ₃ ; the mixture was extracted with EtOAc (3x25 ml). The combined organic extracts were washed with water and brine (15 ml each), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was subjected to chromatography (SiO ₂ ;

continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound as a white foam (1.10 g, 2.6 mmol, 92% yield).

MS (ESI) m/z: 425.1 (M+2+H)+.

8C. Methyl (1 S,3 S)-3-((6-(5-(cyanomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane -1 -carboxylate

To a solution of Example 238B (1.10 g, 2.60 mmol) in MeCN (10 mL) was added NaCN (0.127 g, 2.60 mmol) in DMSO (10 mL) portionwise. The reaction mixture was stirred at 0°C for 30 min, then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3x20 ml). The combined organic extracts were concentrated in vacuo. The crude product was chromatographed (SiO ₂ ; continuous gradient from 0 to 100% EtOAc in hexanes over 20 min) to give the title compound as a white solid (0.864 g, 2.34 mmol, 90% yield).

MS(+) MS = 370.2.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28-7.77 (m, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.79-4.55 (m, 3H), 4.20 (s, 3H), 3.72 ( s, 3Н), 3.06-2.72 (m, 1H), 2.53 (s, 3Н), 2.25-2.08 (m, 1H), 2.03-1.59 (m, 7H).

238D. Methyl (1S,3S)-3-((6-(5-(2-aminoethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3yl)oxy)cyclohexane -1 -carboxylate

To a solution of the compound from example 238C (155 mg, 0.42 mmol) in MeOH (5 ml) was added NiCl ₂ -6H ₂ O (10 mg, 0.042 mmol) and NaBH 4 (32 mg, 0.84 mmol). The reaction mixture was stirred at 0°C for 1 h; water was added and the mixture was extracted with EtOAc (3x10 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by preparative LC/MS: column: Waters XBridge C18, 19x200 mm, 5 µm particles; Guard column: Waters XBridge C18, 19x10 mm, 5 µm particles; mobile phase A: 5:95 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 95:5 MeCN:H ₂ O with 0.1% TFA; gradient: 50-90% B over 20 min, then hold for 5 min at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and concentrated in vacuo by centrifugal evaporation to give the title compound. (130 mg; 0.35 mmol, 83% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 8.99 (br s, 1H), 8.63 (br s, 1H), 7.83-7.70 (m, 1H), 7.62 (d, J=9.0 Hz, 1H), 4.79 (br s, 1H), 4.08 (s, 3H), 3.72 (s, 3H), 3.37 (br d, J=5.1 Hz, 4H), 2.84 (br d, J=4.6 Hz, 1H), 2.56 (s, 3H ), 2.16-2.02 (m, 2H), 2.00-1.84 (m, 2H), 1.82-1.56 (m, 4H).

Example 238.

To a solution of the compound of Example 238D (8 mg, 0.021 mmol) in THF/saturated aqueous NaHCO ₃ (1 ml each) was added 2-phenylacetyl chloride (3.3 mg, 0.021 mmol). The reaction mixture was stirred at room temperature for 1 h, then EtOAc (2 ml) was added. The aqueous layer was extracted with EtOAc (2x1 ml). The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the crude 2-phenylacetamide ester (LCMS [M + H] ⁺ = 492.3) which was used in the next step without further purification. The crude product was dissolved in THF (1 ml) and 2M aq. LiOH (60 µl, 0.12 mmol). The reaction mixture was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was dissolved in H ₂ O (1 ml); the pH was adjusted with 1N HCl to ~3 and the mixture was extracted with EtOAc (2x1 ml). The combined organic extracts were washed with brine (1 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by preparative LC/MS: column: Waters XBridge C18, 19x200 mm, 5 µm particles; Guard column: Waters XBridge C18, 19x10 mm, 5 µm particles; mobile phase A: 5:95 MeCN:H ₂ O with 0.1% TFA; mobile phase B: 95:5 MeCN:H ₂ O with 0.1% TFA; gradient: 50-90% B over 20 min, then hold for 5 min at 100% B; flow rate:

- 137 -

Claims (17)

20 ml/min. Fractions containing the desired product were combined and concentrated in vacuo by centrifugal evaporation to give the title compound as a colorless oil. (6.9 mg, 0.012 mmol, 54.1% yield). LCMS [M+H]+ = 478.1. 1H NMR (DMSO-d6) δ: 8.10 (br s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.46 (br d, J=8.6 Hz, 1H), 7.22-7.29 (m, 2H) , 7.13-7.22 (m, 3H), 4.74 (br s, 1H), 3.89 (s, 3H), 3.21-3.65 (m, 2H), 2.60 (br s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 1.97 (br d, J=13.5 Hz, 1H), 1.75-1.92 (m, 4H), 1.60-1.71 (m, 2H), 1.49-1.60 (m, 2H). hLPA ₁ IC ₅₀ = 138 nM. The compounds of the examples in the following table were synthesized according to the procedures described for the preparation of the compound of example 238. Ex. No. Structure and title Analytical and biological data 239 (18.38)-3-((2-methyl-6-(1-methyl-5-(2(3,5,5-trimethylhexanamido)etyl) -1H1,2,3-triazo l-4- yl)pyride in-3yl)oxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) LCMS [M + H] ⁺ = 500.1; Ή NMR (DMSO-d ₆ ) δ: 7.91 (br s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 4.75 (br s, 1H), 4.00 (s, 3H), 3.253.59 (m, 2H), 2.61-3.01 (m, 2H), 2.55 (s, 4H), 2.47 (s, 2H), 1.92-2.08 (m, 2H), 1.76- 1.91 (m, 5H), 1.47-1.71 (m, 4H), 1.11-1.22 (m, 1H), 0.98 (dd, J=14.0, 6.4 Hz, 1H), 0.84 (s, 8H), 0.81 (br d , J=6.4 Hz, 2H); hLPAi IC ₅₀ = 1021 nM. 240 (18.38)-3-((2-methyl-6-(1-methyl-5-(2(4-methylpentanamido)ethyl)- 1H-1,2,3triazol-4-yl)pyridin-3-yl )hydroxy) cyclohexane-1-carboxylic acid LCMS, [M + H] ⁺ = 458.1; Ή NMR (DMSO-d ₆ ) δ: 8.02 (brt, J-5 3 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.65-4.92 (m, 1H), 3.99 (s, 3H), 3.37 (br s, 1H), 3.21-3.30 (m, 1H), 2.60-2.68 (m, 1H), 2.55-2.59 (m, 1H), 2.45 ( s, 3H), 2.02 (brd, J=14.0 Hz, 1H), 1.90-1.97 (m, 2H), 1.87 (brd, J=13.4 Hz, 1H), 1.75-1.83 (m, 2H), 1.601.67 (m, 2H), 1.46-1.59 (m, 2H), 1.341.42 (m, 1H), 1.23-1.30 (m, 2H), 1.17 (t, J=7.3 Hz, 1H), 0.78 (d , J=6.7 Hz, 6H); hLPAi IC ₅₀ = 1012 nM. Other features of the invention should become apparent from the above description of exemplary embodiments, which are given to illustrate the invention and are not intended to limit it. The present invention may be embodied in other specific forms without departing from the spirit or essential features thereof. This invention covers all combinations of the preferred aspects of the invention noted here. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the embodiments is its own independent embodiment. In addition, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe a further embodiment. CLAIM 1. Compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R ^2a represents hydrogen, chlorine, fluorine or C ₁ _ ₄ alkyl; - 138 042829 R ³ is hydrogen or O _1-6 alkyl; R ⁴ is C _1-10 alkyl, C _3-8 cycloalkyl, phenyl, -(C _1-6 alkylene)-(C _3-8 cycloalkyl) or -(C _1-6 alkylene)-(phenyl) wherein alkyl, cycloalkyl and phenyl, alone or as part of another moiety, are each independently substituted with 0-3 R ⁸ ; R ⁶ is hydrogen or O _1-6 alkyl or each R ⁸ is independently deuterium, halo, hydroxy, amino, cyano, C _1-6 alkyl or C _1-6 deuterated alkyl (fully or partially deuterated). 2. A compound according to claim 1, wherein R ⁶ is methyl or ethyl. 3. Connection selected from: or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, which is: 6. The compound according to claim 1, which is: - 139 042829 or a pharmaceutically acceptable salt thereof. 7. Connection, which is: 8. Connection, which is: or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, which is: 10. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 1, which is: 12. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 1, which is: - 140 042829 14. A pharmaceutical composition for the treatment of a disease, disorder or condition associated with lysophosphatidic acid receptor 1 (LPA1) dysregulation, comprising one or more compounds according to any one of claims 1 to 13, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or diluent. 15. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to π. 14 for the treatment of a disease, disorder, or condition associated with lysophosphatidic acid receptor 1 (LPA1) dysregulation, wherein the disease, disorder, or condition is selected from: (A) pathological fibrosis, where pathological fibrosis is fibrosis of the lungs, liver, kidneys, heart, dermis, eyes or pancreas; transplant rejection; cancer, where the cancer is cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, genitals, urogenital tract, head, kidney, larynx, liver , lung, muscle, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, colon, stomach, testis, or thyroid; osteoporosis or inflammatory disorder; or (B) idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, and systemic sclerosis. 16. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 for the treatment of fibrosis in a mammal in need thereof, wherein the fibrosis is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH) , chronic kidney disease, diabetic kidney disease and systemic sclerosis. 17. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 for the treatment of pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury , chronic kidney disease, liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, colorectal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer-related pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagenosis, atherosclerosis, Raynaud's phenomenon, or neuropathic pain in a mammal in need of this. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 141 -